Osmotic system having laminar arrangement for programming delivery of active agent

ABSTRACT

An osmotic system for delivering an agent is disclosed. The system comprises a wall surrounding a compartment and has a passageway for delivering agent from the compartment. The wall is formed of a laminae comprising a lamina consisting of a multiplicity of materials in laminar arrangement with a lamina consisting of a material or of a multiplicity of materials to provide a laminated wall that is permeable to agents and maintains its integrity during the delivery of agent. The compartment contains an agent that is soluble in an external fluid and exhibits an osmotic pressure gradient across the wall against the fluid, or the agent has limited solubility in the fluid and is mixed with an osmotically effective compound soluble in the fluid and exhibits an osmotic pressure gradient across the wall against the fluid. In operation, agent is released from the system by fluid being imbibed through the wall into the compartment at a rate controlled by the permeability of the wall and the osmotic pressure gradient across the wall producing a solution containing agent, or a solution of compound containing agent which solution in either operation is released through the passageway at a controlled and continuous rate over a prolonged period of time.

FIELD OF THE INVENTION

This invention pertains to an osmotic system in the form of an osmoticdevice. More particularly, the invention relates to an osmotic systemcomprising a laminated wall formed of at least one semipermeable laminaconsisting of a multiplicity of materials laminated to a semipermeablelamina consisting of a material or of a multiplicity of materials fordelivering an active agent at a controlled and continuous rate over aprolonged period of time.

BACKGROUND OF THE INVENTON

Osmotic systems in the form of osmotic devices for delivering abeneficial agent to an environment of use are known to the art in U.S.Pat. Nos. 3,845,770 and 3,916,899. The systems disclosed in thesepatents are made with a wall that surrounds a compartment containing anagent. The wall is permeable to an external fluid, substantiallyimpermeable to agent, and has a passageway for delivering agent. Thesesystems are extraordinarily effective for delivering an agent that issoluble in the fluid and exhibits an osmotic pressure gradient acrossthe wall against the fluid, and also for delivering an agent that haslimited solubility in the fluid and is mixed with an osmoticallyeffective compound that is soluble in the fluid and exhibits an osmoticpressure gradient across the wall against the fluid. The systems releaseagent by fluid being continuously imbibed through the wall into thecompartment at a rate determined by the permeability of the wall and theosmotic pressure gradient across the wall to produce a solution ofsoluble agent, or a solution of soluble compound containing agent whichsolution in either operation is dispensed at a controlled and continuousrate over a prolonged period of time. While the above systems representan outstanding and pioneer advancement in the delivery art, and whilethey are useful for dispensing innumerable agents to an environment ofuse, it has now been found the systems can have a laminated wall thatunexpectedly improves the usefulness and integrity of the systems.

That is, the systems can have a laminated wall that permits propertiessuch as permeability to fluids, impermeability to agents and compounds,and physical and chemical integrity be selected independently, and alsohave the mode of agent release made programmable based on the laminaecomprising the wall. For example, the wall can comprise a laminaeconsisting of a lamina facing a compartment and a lamina facing anenvironment with each possessing different properties. The lamina facingthe compartment housing ingredients such as agents, osmotic compoundsand solutions thereof, that can slowly attack and cause the lamina toloose its integrity can be made inert by formulating it with materialsresistant to attack therefrom, while the lamina facing the environmentcan be formed of different materials inert to the environment, and whichlamina optionally is not contacted by the ingredients, and if it isexposed thereto, it does not interact therewith.

OBJECTS OF THE INVENTION

Accordingly, it is an immediate object of this invention to provide anosmotic system for the controlled and continuous delivery of an activeagent over a prolonged period of time which system is an improvementover the systems known to the prior art.

Another object of the invention is to provide an osmotic systemcomprising a laminated wall formed of at least two laminae made of amultiplicity of materials which laminae maintain their physical andchemical integrity during the controlled and continuous dispensing of anagent over a prolonged period of time.

Yet another object of the invention is to provide an osmotic systemcomprising a laminated wall comprising a semipermeable lamina formed ofa multiplicity of materials and a semipermeable lamina formed of amaterial which laminae are non-erodible and inert during the dispensingof an agent.

Still a further object of the invention is to provide an osmotic systemhaving a wide spectrum of laminated walls in which properties such asfluid transmission rate and resistance to attack may be independentlycontrolled and regulated to a particular application.

Still another object of the invention is to provide an osmotic systemhaving a laminated wall that has a programmable flux rate to fluids, ahigh degree of exclusion towards agents and compounds, and resistance tohydrolysis over a wide pH range.

Still another object of the invention is to provide an osmotic systemfor administering drug where the dose administered contains the intendedquantity and is administered at the correct rate to ensure the requiredonset, intensity and duration of biological response.

Yet still another object of the invention is to provide an osmoticsystem for administering a drug wherein the drug is administered as asolution eliminating in vivo dissolution as a controlling mechanism, andproviding the drug in the most readily available form for absorption.

Still another object of the invention is to provide an osmotictherapeutic system having a laminated wall that makes the systemprogrammable and versatile, and allows a wider control over the ratedrug is released to a drug receptor site.

Other objects, features and advantages of the invention will be moreapparent to those skilled in the art from the following detailedspecification, taken in conjunction with the drawings and theaccompanying claims.

STATEMENT OF THE INVENTION

This invention concerns an osmotic system for dispensing an agent. Thesystem comprises a laminated wall surrounding a compartment and has apassageway for dispensing agent. The compartment contains an agent thatis soluble in an external fluid and exhibits an osmotic pressuregradient across the wall against the fluid, or it contains a mixture ofagents having limited solubility in the fluid and an osmoticallyeffective compound soluble in fluid that exhibits an osmotic pressuregradient across the wall against the fluid. The wall is permeable tofluid, impermeable to agent and compound, and inert towards agent,compound and the environment of use. The wall comprises at least twolamina, one formed of a semipermeable lamina material blended with otherlamina forming materials, and one formed of a semipermeable laminamaterial, or of a semipermeable lamina material blended with otherlamina forming materials. Agent is released from the system by fluidbeing imbibed through the laminated wall into the compartment at a ratecontrolled by the permeability of the wall and the pressure gradientacross the wall producing a solution containing agent that is releasedthrough the passageway at a controlled and continuous rate over aprolonged period of time.

BRIEF DESCRIPTION OF THE DRAWINGS

In the drawings, which are not drawn to scale, but are set forth toillustrate various embodiments of the invention, the figures are asfollows:

FIG. 1A is a view of an osmotic therapeutic system designed for orallydelivering a beneficial agent;

FIG. 1B is a view of the osmotic therapeutic system of FIG. 1A in openedsection illustrating a laminated wall and a compartment of the system;

FIG. 1C is a perspective view of a portion of the laminated wall of FIG.1B with one end peeled open showing the semipermeable laminae that formthe wall;

FIG. 2A is a view of an osmotic therapeutic system manufactured foradministering drug in the anus with the system illustrated in halvedsection for elucidating structural details thereof;

FIG. 2B is a view of the osmotic therapeutic system of FIG. 2Aosmotically administering drug in the environment of use;

FIG. 3 is a view of an osmotic therapeutic system manufactured fortopically administering a drug;

FIG. 4 is a front view of the human eye illustrating an osmotic ocularsystem in operative position in the eye;

FIG. 5 is a graph comparing a lamina that is inert with a lamina thatslowly loses its integrity in the presence of agent;

FIG. 6 is a graph comparing the fluid flux through a lamina thatmaintains its integrity in the presence of fluid with a lamina thatslowly loses its integrity in the presence of fluid;

FIG. 7 is a graph representing the permeability of a series of lamina toa series of compounds; and,

FIG. 8 represents the increase in fluid permeability of a materialcontaining a flux enchancer.

In the drawings and specification, like parts in related figures areidentified by like numbers. The terms appearing earlier in thespecification and in the description of the drawings, as well asembodiments thereof, are further detailed elsewhere in the disclosure.

DETAILED DESCRIPTION OF THE DRAWINGS

Turning now to the drawings in detail, which are examples of variousosmotic systems of the invention, and which examples are not to beconstrued as limiting, one embodiment of an osmotic system is indicatedin FIGS. 1A, 1B and 1C considered together by the numeral 10. In FIGS.1A and 1B an osmotic system 10 in the form of an oral, osmotictherapeutic system is comprised of a body 11 having a semipermeablelaminated wall 12 that surrounds a compartment 13, seen in FIG. 1B inopened section with a portion of wall 12 removed at 14. System 10 has apassageway 15 in wall 12 that extends through 12 and communicates withcompartment 13 and the exterior of system 10. Compartment 13, as seen inFIG. 1B, is a means for containing a beneficial agent 16 that is solublein an external fluid and exhibits an osmotic pressure gradient acrosswall 12 against an external fluid or, compartment 13 optionally containsa mixture of agents 16 with at least one agent exhibiting an osmoticpressure gradient. In another embodiment, compartment 13 contains anagent that has limited solubility or is substantially insoluble in theexternal fluid and is mixed with an osmotically effective compound 17that is soluble in the external fluid and exhibits an osmotic pressuregradient across wall 12. Compartment 13 optionally contains othercompounds such as a surfactant for wetting the agent, a gelling orsuspending agent to displace the active agent from the compartment, or anon-toxic dye for identifying agent 16 and for making release of agent16 visible to the unaided eye.

Wall 12, as seen in FIG. 1C, represents a section removed from system 10of FIG. 1B, and it is separated at 18 for illustrating the laminatedstructure of wall 12. Wall 12 comprises a lamina consisting of anexterior, semipermeable lamina 19 and an interior semipermeable lamina20. Lamina 19, in one embodiment, is a composite comprising at least twomaterials blended to form a lamina that is, (a) permeable to the passageof an external fluid, (b) maintains its physical and chemical integrityin the environment of use, and is more particularly substantiallynon-erodible and inert in the environment, (c) provides mechanicalsupport for other laminae comprising wall 12, and (d) optionally issubstantially impermeable to compounds present in the environment ofuse. Lamina 19, in another embodiment is formed of a semipermeablematerial and has the properties described in (a) through (d).

Lamina 20, in one embodiment, is a composite comprising at least twomaterials blended to form a semipermeable lamina that is, (e) permeableto the passage of an external fluid, (f) substantially impermeable tothe passage of agent and compound present in the compartment, (g)maintains its physical and chemical integrity in the presence of agentand more particularly is substantially non-erodible and inert in thepresence of agent, (h) provides mechanical support for other laminaeforming wall 12, and (i) it is substantially impermeable to compoundspresent in the environment of use. Lamina 20, in another embodiment, isformed of a single semipermeable material having the properties of (e)through (i). Also according to the instant invention, at least one oflaminae 19 or 20 is a composite endowed with the above describedproperties, with the lamina positioned facing the compartment in apresently preferred embodiment more hydrophobic, more inert, having ahigher degree of agent and compound rejection, and having a decreasedpermeability to the passage of an external fluid. While laminae 19 and20 in a presently preferred lamination were described with lamina 20positioned facing compartment 13 and lamina 19 positioned distant fromcompartment 13, it is understood for other embodiments and applications,lamina 20 can be the exterior surface of system 10 distant fromcompartment 13, and lamina 19 can be the interior surface of laminatedwall 12. A detailed description of laminae forming materials, agents andcompounds is presented later in the specification.

In operation, system 10 in one embodiment releases agent 16 contained incompartment 13 and soluble in the external fluid by fluid being imbibedinto compartment 13 in a tendency towards osmotic equilibrium at a ratecontrolled by the permeability of laminated wall 12 and the osmoticpressure gradient across wall 12 to continuously dissolve agent 16 whichis osmotically pumped from system 10 throgh passageway 15 at acontrolled and continuous rate over a prolonged period of time. System10, in another embodiment, releases agent 16 that has limited solubilityin the fluid and is mixed with an osmotically effective compound byfluid being imbibed through wall 12 into compartment 13 in a tendencytowards osmotic equilibrium at a rate controlled by the permeability ofwall 12 and the osmotic pressure gradient across wall 12 to continuouslydissolve the osmotically effective compound to form a solutioncontaining agent that is released from system 10 through passageway 15at a controlled and continuous rate over a prolonged period of time.

Osmotic system 10 of FIGS. 1A through 1C can be made into many usefulembodiments including the presently preferred embodiment for oral use.The oral system is useful for releasing in the gastrointestinal tracteither a locally or systemically acting agent over a prolonged period oftime. Osmotic, oral therapeutic system 10 can have various conventionalshapes and sizes such as round with a diameter of 3/16 inches to 1/2inches, or it can be shaped like a capsule having a range of sizes fromtriple zero to zero, and from 1 to 8.

FIGS. 2A and 2B represent another osmotic system 10 manufacturedaccording to the invention for administering a drug to a drug receptor.In the illustrated embodiment, system 10 is designed for placement anddrug release in an anus 22 of a patient 21. System 10 consists of arelatively long and relatively small diameter tubular body 11 made withrounded ends 21a for easily placing system 10 in anus 22, as seen inFIG. 2B. System 10, seen in halved-section at 23, is structurallyidentical to system 10 described above and it operates in a like manner.System 10 is comprised of a laminated wall 12 formed of a pair oflaminae 19 and 20 surrounding and forming compartment 13 for containinga drug, not shown. A passageway 15 connects compartment 13 with theexterior of system 10 for releasing a locally or systemically actingdrug to anus 22. System 10 in another embodiment can be sized, shapedand adapted for placement in vagina 26 of patent 21 for releasing a drugor fragrence in vagina 26. Other anatomical features of patient 21illustrated in FIG. 2B are rectum 24, bladder 27 and urethra 28.

FIG. 3 represents another system 10 designed for administering a drug.In FIG. 3, system 10 is mounted on a drug receptor site 29, an arm ofhuman 30, for administering drug locally or systemically by absorptionor drug penetration. System 10 is comprised of a non-toxic laminatedwall 12 formed of a pair of semipermeable laminae 19 and 20 thatsurrounds and forms a circle shaped compartment. The compartmentcontains an agent, or optionally a mixture of agent and an osmoticallyeffective compound. Wall 12 has a curvature that corresponds to thecurvature of site 29 for proper placement on site 29. System 10 has apassageway positioned on its under surface for releasing drug to site29. System 10 is equipped with a band and buckle 31 that circles the armfor holding system 10 thereon. System 10 is structured and operates aspreviously described, and it administers drug at a controlled andcontinuous rate to site 29 for a prolonged period of time.

Referring to FIG. 4, an ocular therapeutic system 10 is seen in eye 32for administering drug at an osmotically metered dosage rate thereto. InFIG. 4, eye 32 is comprised of an upper eyelid 33 with eyelashes 34, alower eyelid 35 with eyelashes 36, and an eyeball 37 covered for thegreater part by sclera 38 and at its center area by cornea 39. Eyelids33 and 35 are lined with an epithelial membrane or palpebralconjunctiva, sclera 38 is lined with a bulbar conjunctiva that coversthe exposed surface of eyeball 37, and cornea 39 is covered with atransparent epithelial membrane. The portion of the conjunctiva whichlines upper eyelid 33 and the underlying portion of the bulbarconjunctiva defines an upper cul-de-sac, while that portion of thepalpebral conjunctiva which lines the lower eyelid 35 and the underlyingportion of the bulbar conjunctiva defines a lower cul-de-sac. Ocularosmotic system 10, seen in broken lines, is shaped, sized and adaptedfor placement in the upper or lower cul-de-sac. System 10 is seen in thelower cul-de-sac and it is held in place by the natural pressure oflower eyelid 35. System 10 contains an ophthalmic drug for release toeye 32 at a controlled and continuous rate over a prolonged period oftime.

Ocular system 10 can have any geometric shape that fits comfortably inthe cul-de-sac. Typical shapes include ellipsoid, bean, banana,circular, rectangular, doughnut, crescent and half-ring shaped systems.In cross-section, the system can be doubly convex, concavo-convex,rectangular and the like, as the device in use will tend to conform tothe shape of the eye. The dimensions of an ocular system can vary widelywith the lower limit governed by the amount of drug to be supplied tothe eye as well as by the smallest sized system that can be placed intothe eye. The upper limit on the size of the system is governed by thespace limitation in the eye consistent with comfortable retention in theeye. Satisfactory systems generally have a length of 4 to 20millimeters, a width of 1 to 15 millimeters. The ocular system cancontain from 0.15 micrograms to 100 milligrams of drug, or more, and itis made from non-erodible and inert materials that are compatible withthe eye and its environment.

While FIGS. 1 through 4 are illustrative of various systems that can bemade according to the invention, it is to be understood these systemsare not to be construed as limiting, as the systems can take a widevariety of shapes, sizes and forms for delivering agent to differentenvironments of use. For example, the systems include buccal,intramuscular implant, nose, artificial gland, anus, rectum, cervical,intrauterine, arterial, venous, vaginal, and ear systems. The systemsalso can be adapted for delivering an active agent in streams,aquariums, fields, factories, reservoirs, laboratory facilities, hothouses, transportation means, navel means, air and military means,hospitals, veterinary clinics, nursing homes, chemical reactions, andother environments of use.

DETAILED DESCRIPTION OF THE INVENTION

In accordance with the practice of the invention, the terms used hereindenote the following: the terms "osmotic delivery system" and "osmoticdelivery system in the form of an osmotic device" are deemed asfunctional equivalents and generically they are osmotic devices. Theseterms also include "osmotic therapeutic systems" and "systems". Thephrase "maintains its physical and chemical integrity" means thelaminated wall and the laminae keep their constitution and generalpreselected design and shape in the environment of use and in thepresence of agent during the period of agent release even though thesystem may be flexible and resilient. The terms "non-erodible", "resisterosion", "resist bioerosion", and "inert" mean the laminated wall andthe laminae are substantially resistant and free from chemical,enzymatic and biological attack and reaction in the environment of useand in the presence of agent. The expression "laminated wall" means thewall of the system is comprised of at least two laminae in laminararrangement acting in concert to form an integral, unit wall that doesnot separate into laminae during the operative history of the system.The term "composite" means a lamina formed of a blend of materials thatproduce an operative, semipermeable lamina useful for manufacturing alaminated wall. The expression "formed of a multiplicity of materials"means a semipermeable lamina formed of at least two materials thatproduce a composite lamina. The phrases "a semipermeable lamina formingmaterial", or "a single semipermeable polymeric lamina forming material"means this lamina is formed of a semipermeable homopolymer or of asemipermeable copolymer. The term "hydrophobic" means a semipermeablepolymer when placed in water for 24 hours does not absorb it in anamount exceeding 10 percent of its dry weight.

Further, in accordance with the practice of the invention, it has nowbeen discovered that osmotic delivery systems can be manufactured with alaminated wall comprised of at least two different laminae selected fromthe group consisting of laminae formed of a material and laminae formedof a blend of materials. Materials suitable for forming laminaeconsisting of a single material are generically polymeric materials. Thepolymeric materials are homopolymers and copolymers and they includematerials known as semipermeable, osmosis and reverse osmosis materials.Laminae 19 and 20 when formed of a material are independently selectedfrom semipermeable homopolymers and semipermeable copolymers whichgenerically include polysaccharides comprised of anhydroglucose units.In one embodiment, the polysaccharides are cellulose esters having adegree of substitution, d.s., on the anhydroglucose unit from greaterthan 0 up to 3 inclusive. By "degree of substitution" as used herein ismeant the average number of hydroxyl groups on the anhydroglucose unitof the polymer replaced by a substituting group. Exemplary materials arerepresented by Formula 1: ##STR1## wherein R₁, R₂ and R₃ are the same ordifferent and they are selected from the group consisting of hydrogenand acyl, ##STR2## with at least one or all of R₁, R₂ and R₃ in theanhydroglucose unit either partially or completely substituted with theacyl moiety. The acyl moiety at R₁, R₂ and R₃ can be the same ordifferent; and, R₄ is a member selected from the group consisting ofhydrogen, alkyl groups of the straight or branched chain type havingfrom 1 to 20 carbons and alkenyl groups that are straight or branchedand have from 2 to 20 carbon atoms. Typical acyl moieties includealkanoyl and alkenoyl such as formyl, acetyl, propionyl, butyryl,hexanoyl, heptanoyl, octanoyl, undecanoyl, lauroyl, palmitoyl, stearoyl,oleoyl, and isomeric forms thereof; and n in a presently preferredembodiment is a positive number greater than 5.

Representative materials embraced by Formula 1 include polymericcellulose esters and copolymeric cellulose esters such as mono, di, andtricellulose acylates. Exemplary polymers include cellulose acetatehaving a D.C. up to 1 and an acety content of up to 21%; cellulosediacetate having a D.S. of 1 to 2 and an acetyl content of 21 to 35%;cellulose triacetate having a D.S. of 2 to 3 and an acetyl content of 35to 44.8%; cellulose propionate having a D.S. of 1.8 and a propionylcontent of 38.5%; cellulose acetate propionate having an acetyl contentof 1.5 to 7% and a propionyl content of 39 to 42%; cellulose acetatepropionate having an acetyl content of 2.5 to 3%, an average combinedpropionyl content of 39.2 to 45% and a hydroxyl content of 2.8 to 5.4%;cellulose acetate butyrate having a D.S. of 1.8, an acetyl content of 13to 15 %, and a butyryl content of 34 to 39%; cellulose acetate butyratehaving an acetyl content of 2 to 29.5%, a butyryl content of 17 to 53%,and a hydroxyl content of 0.5 to 4.7%; cellulose triacylates having aD.S. of 2.9 to 3 such as cellulose trivalerate, cellulose trilaurate,cellulose tripalmate, cellulose trisuccinate, cellulose triheptylate,cellulose tricaprylate, cellulose trioctanoate, and cellulosetripropionate; cellulose diesters having a lower degree of substitutionand prepared by the hydrolysis of the corresponding triester to yieldcellulose diacylates having a D.S. of 2.2 to 2.6 such as cellulosedisuccinate, cellulose dipalmitate, cellulose dioctanoate, cellulosedicaprylate, and cellulose dipentanate; and esters prepared from acylanhydrides or acyl acids in an esterification reaction to yield esterscontaining different acyl groups attached to the same cellulose polymersuch as cellulose acetate valerate, cellulose acetate succinate,cellulose propionate succinate, cellulose acetate octanoate, cellulosevalerate palmitate, cellulose acetate palmitate, and cellulose acetateheptanoate. Generally, materials useful for forming the laminated walland the laminae will have a fluid permeability of 10.sup.⁻⁵ to 10.sup.⁻¹(cc mil/cm² hr atm), expressed per atmosphere (atm) of hydrostatic orosmotic pressure difference across the wall or lamina at the temperatureof use while possessing a high degree of impermeability to solute areuseful for the purpose of the invention. The polymers described aboveare known to the art or they can be prepared according to the proceduresin Encyclopedia of Polymer Science and Technology, Vol. 3, pages 325 to354, 1964, published by Interscience Publishers Inc., New York.

Laminae 19 and 20 also can be independently selected from semipermeablehomopolymers and semipermeable copolymers embraced by Formula 2 asfollows: ##STR3## wherein R₅ is a member selected from the groupconsisting of hydroxyl; alkoxy; alkoxy substituted with a memberselected from the group consisting of alkyl, alkoxy, halogen and cyano;alkylcarbonate; alkylcarbamate; alkylsulfonate; alkylsulfamate;oxalkyleneoxycarboalkyl; acyloxy including alkanoyloxy, alkenoyloxy andaroyloxy; alkanoyloxy substituted with an alkoxy, halogen, carboalkyl,carboalkoxy and cyanoalkoxy; aroyloxy substituted with a halo, carboxy,carboalkyl and cyano; furoyloxy, and n is a positive integer greaterthan 5, usually 10 to 3 × 10⁶.

Exemplary groups representative of R₅ of Formula 2 are as follows: by"alkyl" is meant straight or branched chain alkyl radicals of 1 to 20carbon atoms inclusive, such as methyl, ethyl, n-propyl, iso-propyl,n-butyl, sec-butyl, pentyl, neo-pentyl, n-hexyl, iso-hexyl, heptyl,4,4-dimethyl pentyl, 2,2,4-trimethylpentyl, and nonyl. By "alkenyl" ismeant straight or branched chain alkenyl groups of 2 to 20 carbons suchas 1-propenyl, 2-propenyl or allyl, 1-butenyl, 2-butenyl, 1-pentenyl,and the corresponding positional isomers such as 1-isobutenyl,2-isobutenyl, 2-sec-butenyl, 2-methyl-1-butenyl, 2-methyl-2-pentyenyland 2,3-dimethyl-3-hexenyl. The term "alkoxy" as used for R₅ includedthe straight and branched chain alkoxy groups having 1 to 20 carbonsinclusive, for example, methoxy, ethoxy, propoxy, butoxy, n-pentoxy,n-hexoxy, isopropoxy, 2-butoxy, isobutoxy, 3-pentoxy, and n-octoxy.Exemplary halogen include fluorine, chlorine and bromine. Exemplary arylinclude phenyl and naphthyl. Exemplary alkylene as a linking moietywithin a substituent are alkylenes of 2 to 10 carbons such as1,2-ethylene, 1,3-propylene, 1,2-propylene, 1,4-butylene, 1,5-pentylene,1,6-hexylene, 1,7-heptylene and 1,10-decylene. Exemplary alkanoyloxy,alkenoyloxy and aroyloxy include formyloxy, acetyloxy, propionyloxy,valeryloxy, heptanoyloxy, octanoyloxy, undecanoyloxy, lauroyloxy,palmitoyloxy, stearoyloxy, oleoyloxy, acryloyloxy, methacryloyloxy,crotomyloxy, 3-butenoyloxy, benzoyloxy, phenylacetyloxy, cinnamoyloxynaphthoyloxy, p-ethoxybenzyloxy, alloxyphenylacetyloxy, furoyloxy,p-nitrobenzoyloxy and chlorophenoxyacetyloxy.

The laminae forming materials embraced by Formula 2 includepolysaccharide materials having a degree of substitution on theanhydroglucose unit greater than from 0 up to 3 inclusive with thesubstituents R₅ the same or different and bonded to a common mer. Thematerials can be polymeric cellulose esters or polymeric celluloseethers. The monomeric unit can be substituted with like ester groups,with different ester groups, with like ether groups, with differentether groups and with different ester and ether groups bonded to thesame mer to give a homopolymer or copolymer. Typical materialsrepresented by Formula 2 include cellulose acetate acetoacetate,cellulose acetate chloroacetate, cellulose acetate furoate,dimethoxyethylcellulose acetate, cellulose acetatecarboxymethoxypropionate, cellulose acetate phthalate, cellulosebutyrate naphthylate, cellulose acetate benzoate, methylcelluloseacetate, methylcyanoethyl cellulose, cellulose acetate methoxyacetate,cellulose acetate, cellulose acetate ethoxyacetate, cellulose acetatedimethylsulfamate, ethylcellulose dimethylsulfamate, cellulose acetatep-toluene sulfonate, cellulose acetate methylsulfonate, celluloseacetate dipropylsulfamate, cellulose acetate butylsulfonate, celluloseacetate dimethylaminoacetate, cellulose acetate ethyloxalate, celluloseacetate laurate, cellulose butyrate furoate, cellulose stearate,cellulose resinate, cellulose acetate methylcarbonate, cellulose acetateethylcarbonate, cellulose acetate methylcarbamate, and cellulose acetateethylcarbamate.

The semipermeable laminae forming materials also include celluloseethers such as alkylcellulose, methylcellulose, ethylcellulose,ethylmethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose,hydroxyethyl methylcellulose, hydroxypropyl methylcellulose,ethylhydroxy ethylcellulose, hydroxybutyl methylcellulose,cyanoethylcellulose, benzylcellulose, sodium carboxymethylcellulose,sodium carboxymethylhydroxy ethylcellulose, carbamoylethylcellulose,carboxyethylcellulose, phenylcellulose, benzylhydrylcellulose,tritylcellulose, hexylpropylcellulose, carboxylbenzyl cellulose and2-carboxylbenzoyloxy propylcellulose. Methods for preparing thecellulose ethers are disclosed in Encyclopedia of Polymer Science andTechnology, Vol. 3, pages 459 to 549, 1964, published by IntersciencePublishers, Inc., New York.

Other semipermeable materials useful for forming laminae includeacylated polysaccharides and acylated starches such as agar-agaracetate, acylated alginates, amylose triacetate, beta glucan acetate,beta glucan triacetate, acetyl alginate, triacetate of locust bean gum,alkanoyl carrageenin, acylated tragacanth, esterified gum karaya,cellulose derivatives substituted with an inorganic moiety such as anitro group, hydroxylated ethylene vinylacetate, aromatic nitrogencontaining polymeric materials that exhibit permeability to aqueousfluids and substantially no passage to solute, semipermeable membranesmade from polymeric epoxides, copolymers of alkylene oxides and alkylglycidyl ethers, polyvinyl acetate, cross-linked polyvinyl acetate,polyurethanes, film forming materials as disclosed by Loeb andSourirajan in U.S. Pat. No. 3,133,132, cross-linked derivatives ofpolyvinyl alcohol, polyvinyl butyrate, ionically associatedpolyelectrolytes formed by the coprecipitation of a polycation and apolyanion as described in U.S. Pat. Nos. 3,276,586; 3,541,005;3,541,006; 3,546,142; and 3,173,876; polystyrene derivatives such aspoly (sodium styrene sulfonate) and poly(vinylbenzyltrimethyl ammoniumchloride), polyesters, polyamides and polyacrylates. These semipermeablematerials and other semipermeable materials are known to the art anddisclosed in Handbook of Common Polymers by Scott, J. R. and Roff, W.J., 1971, published by CRC Press, Cleveland, Ohio.

Further, in accordance with the invention, laminae 19 and 20 when formedof a blend of materials, consists of materials independently selectedfrom composite lamina forming materials with each lamina comprised of,(1) at least one semipermeable lamina forming material permeable to thepassage of fluid and substantially impermeable to agent and othercompounds blended with at least one or more of the following laminaforming materials, (2) a stabilizing material that imparts physical andchemical integrity to the lamina, and more particularly gives the laminainertness towards agents, compounds and solutions thereof, and tocompounds present in the environment of use, (3) a flux regulator thatgoverns the permeability of fluid through the lamina, (4) a plasticizerthat gives flexibility to the lamina, and (5) a dispersant useful forblending the materials into an operative integral composite lamina. Thelaminated wall's integrity or inertness to agents in the compartment,and to fluids and other compounds in the environment of use can beprecisely regulated by selecting the ingredients blended into compositelaminae forming the laminated wall of the system. The fluid permeabilityof the laminated wall can be regulated in a like manner.

The composite laminae will in a presently preferred embodiment, includeat least one of the semipermeable materials embraced by Formula 1.Laminae 19 and 20 also can include a stabilizing material identifiedabove as 2. This latter material is a different material than thelaminae forming material and it is selected from the materials embracedby Formula 1 and included therewith, or the materials embraced byFormula 2 and included therewith. Also, the semipermeable materials ofFormula 2 and included therewith can be used to form composite laminaewith blended with stabilizing materials. Criterion that can be used forselecting laminae forming materials, stabilizing materials, and othermaterials used to form blends are presented later in the specification.

Suitable laminae for manufacturing laminated osmotic systems can beselected according to the criterion disclosed in U.S. Pat. No. 3,845,770and 3,916,899. This criterion consists in first calculating for alaminate that is to be selected, the permeability to fluid necessary todeliver an amount of agent Q_(p), in mg, in time t, in hours, from asystem having a total laminated area A, in cm², a laminated thickness h,in mils, with the agent having a solubility in the fluid S, in mg/ml(solution), and the agent having an osmotic pressure in the device of π,in atm. The value k is expressed in units ##EQU1## and it is calculatedfrom Equation 1. ##EQU2## Then, after having calculated the desiredlaminated permeability k from Equation 1, laboratory measurements aremade to identify laminates having a permeability k_(o) substantiallyequivalent to the calculated permeability k. The measurements arecarried out by using a standard osmosis cell and measuring the rate offluid flow through a laminate having a known composition and thickness.The flow rate is determined by measuring fluid transport from a firstchamber containing a fluid free of agent through a laminate thatseparates it from a second chamber housing a solution containing a knownconcentration of agent that exhibits an osmotic gradient across thelaminate. Sometimes the chamber contains an osmotically effectivecompound which is used as osmotic driving agent. The flow measurement isperformed by adding to the first chamber the fluid and then adding tothe second chamber, equipped with a stirring bar, the same fluidcontaining agent, and optionally containing the additional osmoticagents. The first chamber is connected through a conduit to a reservoircontaining a supply of fluid and the second chamber is connected to avertically positioned tube of known diameter and calibrated with indiciathat indicate the amount of fluid in the tube. In operation, fluid flowsfrom the first chamber through the laminate into the second chamber byosmosis causing the solution to rise in the tube over time, t, to give avolume displacement, ΔV, during a time interval, Δt. The volume, ΔV, isread on the tube calibrated in cm³, and the time interval, Δt, ismeasured with a stopwatch. The value k₀ π in cm³ mil/cm² hr for thelaminate with permeability, k_(o), for the agent solution with anosmotic pressure, π, is calculated from Equation 2, and wherein A_(o) isthe area of the laminate, in the osmosis cell, and h_(o) is thethickness of this laminate. ##EQU3## If the measured value, k_(o),approximates the calculated value, k, the laminate can be used formanufacturing the osmotic device.

The properties of laminae suitable for forming laminated walls also canbe determined with the osmosis cell. These properties are integralparameters in controlling the release of an agent from systems, asproperties of laminated walls such as permeability to fluids andresistance to passage of agents are the sum of all the properties of theindividual laminae. These properties are expressed by Equation 3.##EQU4## wherein t is the laminated wall, 1, 2 and n are laminae, h_(t)is the thickness of the laminated wall, h₁, h₂ and h_(n) are thethickness of the laminae, (kπ)_(t) is the fluid transmission rate forthe laminated wall and it is the product of permeability of thelaminated wall to fluid times the osmotic pressure, (kπ)₁, (kπ)₂ and(kπ)_(n) have a like meaning for their respective laminae. Otherprocedures and devices useful for measuring fluid permeability andosmotic flow are disclosed in J. App. Poly. Sci., Vol. 9, pages 1341 to1362, 1965; and in Yale J. Biol. Med., Vol. 42, pages 139 to 153, 1970.

Suitable stabilizing materials can be selected from the above materialsfor blending with the lamina forming materials used to form a laminatedwall by those skilled in the art by using the procedures describedbelow. These procedures are the lamina weight loss and the osmosisprocedure. The procedures use lamina formed with stabilizers and formedwithout stabilizers. The lamina weight loss procedure is carried outwith lamina that are cast from solution or optionally melt pressed. Thelamina are solution cast with a Gardner film-casting knife on a cleanglass plate at room temperature with the solution removed by evaporationin an oven at elevated temperatures until the lamina is dry. Next, thelamina is removed from the glass and cut into strips 1 to 10 cm inlength, 1 to 10 cm in width and having a thickness of 1 to 10 mils.Then, after all the strips are cut to have the same area and weight,they are placed in a glass container filled with a solution consistingof a known concentration of agent formulated with the fluid of theenvironment of use. The temperature of the container is made upcorrespond to the temperature of the environment where an osmotic systemformed with the lamina will be placed for releasing agents. At regulartime intervals, strips are taken from the solution, rised in distilledwater, dried in an oven, usually 50° C for 24 hours, and weighed. Theweight of a single strip repeatedly introduced into the solution, or theweight of many strips consecutively removed at different time intervalsare indicated along the ordinate, plotted as a function of timeindicated along the abscissa, such as t₁, t₂, t₃, etc. as shown in FIG.5. In FIG. 5, line 1 represents the results obtained for a lamina thatmaintains its physical and chemical integrity when exposed to agentsolution. That is, the lamina does not lose any weight over time anddemonstrates inertness and resistance to erosion in the presence ofagent solution. In the same Figure, line 2 represents a lamina whichupon exposure to agent solution, demonstrates a weight loss and isundesirable for making an inert portion of a laminated wall of anosmotic system. A stabilizer can be blended into this lamina to enhanceits inertness and resistance and substantially prevent weight lossthereby making the lamina useful for fabricating laminated wall.

In the osmosis procedure, the rate of fluid flow through a lamina orlaminate is measured and it is performed exposing the inert lamina tothe test environment or agent by using an osmosis cell. The purpose ofthe procedure is to ascertain, (1) if a given lamina, or the laminate,maintains its integrity in the presence of fluid and agent, and (2) if astabilizer added to the lamina increases its physical and chemicalintegrity as seen from flux measurements. The procedure is carried outusing the cell according to the above described procedure with thevolume of solution, ΔV, rising in the tube attached to chamber 2measured and plotted as a function of time, t. The data obtained for twodifferent laminae are shown in FIG. 6. In FIG. 6, line 1 represents alamina that maintains its integrity in the presence of fluid and agent.That is, since the rate of fluid flow is substantially constant, thelamina does not undergo any substantial change over time, t. Line 2shows the fluid flux, ΔV/Δt, through a lamina where the rate iscontinually increasing over time. This change indicates the lamina doesnot maintain its integrity in the presence of fluid or agent. For thoseapplications where a change in flux is unwanted, a different laminashould be selected for the system or a stabilizer can be added to thelamina to enhance its inertness. The flux through laminae containingstabilizer is measured as just described. The properties of laminatesalso can be determined with the osmosis cell. Using the abovetechniques, one versed in the art would use the weight loss and osmosisprocedures for ascertaining if the fluid and agent adversely affect thelaminate or laminae, and also for determining if a stabilizer overcomesthis effect. The stabilizer can be added in varying amounts to obtain anacceptable slope as seen in FIGS. 5 and 6, with the stabilizerdecreasing the slope, not shown, indicating a lessening of laminate andlaminae agent solution interaction.

Additional scientific criterions that can be used by those skilled inthe art for selecting a stabilizing material include the following: (a)the material possesses a high degree of substitution, for example, thematerial has undergone etherification or esterification particularlyacylation towards or to completion with lamina formed containing thesestabilizers demonstrate increased resistance to hydrolysis and increasedrejection of agent, (b) the stabilizer exhibits a flux decrease to fluidand solute with increasing molecular size of the substituting group,such as an ether or ester group, (c) the stabilizer exhibits a fluxdecrease proportional to the increase in size of the substituent, forexample, the decrease occurs as the number of carbon atoms increase in ahydrocarbon moiety such as an alkyl or alkoxy moiety, (d) the stabilizerexhibits increased stability with an increase in the degree ofsubstitution of hydrophobic ether and larger hydrophobic ester groupswith an accompanying decrease in the degree of substitution of smallerhydrophilic ester groups, and (e) the stabilizer exhibits a fluxdecrease as the number of polar, ionic groups bonded to the stabilizerdecrease. These principles are exemplified and illustrated in FIG. 7.FIG. 7 is an illustration of the decrease in polymer permeability tosolutes, such as sodium chloride indicated by x, potassium chlorideindicated by Δ, magnesium sulfate indicated by O, and potassium sulfateindicated by , with increasing degrees of substitution by ester groupsincluding acetyl moieties. A lower permeability to solutes signifies ahigher rejection or exclusion of the solute from the polymer network,thereby diminishing the chances for polymer-solute interaction, whileincreasing the stability of the polymer. The trends shown in FIG. 7 forthe indicated solutes hold for other agents.

The expressions "flux enhancing agent," "flux decreasing agent" and"flux regulator" as used herein means a compound that when added tosemipermeable laminae forming material assists in regulating the fluidpermeability or liquid flux through the laminae and the final laminatedwall. The agent can be preselected to increase or decrease the liquidflow. Agents that produce a marked increase in permeability to fluidsuch as water, are often essentially hydrophilic, while those thatproduce a marked decrease to fluids such as water, are essentiallyhydrophobic. The flux regulators in some embodiments also can increasethe flexibility of the laminae and the resulting laminated wall. Theflux regulators in one embodiment, are polyhydric alcohols andderivatives thereof, such as polyalkylene glycols of the formulaH--(O--alkylene)_(n) --OH wherein the bivalent alkylene radical isstraight or branched chain and has from 1 to 10 carbon atoms and n is 1to 500 or higher. Typical glycols include polyethylene glycols 300, 400,600, 1500, 1540, 4000, and 6000 of the formula H--(OCH₂ CH₂)_(n) --OHwherein n is respectively 5 to 5.7. 8.2 to 9.1, 12.5 to 13.9, 29 to 36,29.8 to 37, 68 to 84, and 158 to 204. Other polyglycols include the lowmolecular weight glycols such as polypropylene, polybutylene andpolyamylene.

The flux regulators in another embodiment includepoly(α,ω)-alkylenediols wherein the alkylene is straight or branchedchain of from 2 to 10 carbon atoms such as poly(1,3)-propanediol,poly(1,4)-butanediol, poly(1,5)-pentanediol and poly(1,6)-hexanediol.The diols also include aliphatic diols of the formula HOC_(n) H_(2n) OHwherein n is from 2 to 10 and the diols are optionally bonded to anon-terminal carbon atom such as 1,3-butylene glycol, 1,4-pentamethyleneglycol, 1,5-hexamethylene glycol and 1,8-decamethylene glycol; andalkylenetriols having 3 to 6 carbon atoms such as glycerine,1,2,3-butanetriol, 1,2,3-pentanetriol, 1,2,4-hexanetriol and1,3,6-hexanetriol.

Other flux regulators include esters and polyesters of alkylene glycolsof the formula HO--(alkylene--O)_(n) --H wherein the divalent alkyleneradical includes the straight chain groups and the isomeric formsthereof having from 2 to 6 carbons and n is 1 to 14. The esters andpolyesters are formed by reacting the glycol with either a monobasic ordibasic acid. Exemplary flux regulators are ethylene glycoldipropionate, ethylene glycol butyrate, ethylene glycol diacetate,triethylene glycol diacetate, butylene glycol dipropionate, polyester ofethylene glycol with succinic acid, polyester of diethylene glycol withmaleic acid and polyester of triethylene glycol with adipic acid. Also,certain stabilizers in some embodiments can serve as a flux regulatorparticularly when it has a low D. S. of acyl moities.

Suitable flux regulators for compounding with a material to increase ordecrease its fluid permeability can be selected by blending knownamounts of a regulator with the material, casting the blends into thinlaminae, and then measuring the change in permeability towards the fluidfound in the environment of use. For example, to two separate batches oflamina forming cellulose acetate having an acetyl content of 32% and39.8% were added 1, 2 and 3 grams of flux regulator polyethylene glycolhaving a molecular weight of 400 and the ingredients blended in a highshear blender in the presence of 120 ml of dimethyl formamide to yieldsix blends. Next, the blends were solvent cast with a Gardener knife anddried in an oven for 7 days at 50° C. The water permeability of the sixlaminae was measured in the osmosis cell described above and the resultsrecorded in FIG. 8. In FIG. 8, the triangles represent cellulose acetate32% and the circles represent cellulose acetate 39.8%. Also, as recordedon the ordinate, k_(o) indicates the water permeability throughcellulose acetate 32% free of flux regulator and cellulose acetate 39.8%that did not contain any flux regulator, and k indicates the waterpermeability through cellulose acetate 32% and cellulose acetate 39.8%where both contained the flux regulator. The positive integers 10, 20,30 and 40 recorded on the abscissa, indicate the percent of fluxregulator in the lamina. Using the above technique, specific fluxregulators for blending with specific materials to regulate thepermeability can be selected for making the desired lamina for making alaminated wall. The amount of flux regulator added to a materialgenerally is an amount sufficient to produce the desired permeability,and it will vary according to the lamina forming material and the fluxregulator used to modulate the permeability. Usually, from 0.001 partsup tp 50 parts, or higher of flux regulator can be used to achieve thedesired results, with a presently preferred range consisting of 0.1 partup to 30 parts of regulator or mixtures thereof for 100 parts of laminaforming material.

Exemplary plasticizers suitable for the present purpose genericallyinclude plasticizers that lower the temperature of the second-orderphase transition of the laminae forming materials or the elastic modulusthereof, increase the workability of the laminae of the laminated wall,its flexibility, and its permeability to fluid. Plasticizers operablefor the present purpose include both cyclic plasticizers and acyclicplasticizers. Typical plasticizers are those selected from the groupconsisting of phthalates, phosphates, citrates, adipates, tartrates,sebacates, succinates, glycolates, glycerolates, benzoates, myristates,sulfonamides, and halogenated phenyls. Generally from 0.01 to 100 parts,or higher, of a plasticizer or a mixture of plasticizers areincorporated into 100 parts of lamina forming material.

Exemplary plasticizers further include dialkyl phthalates, dicycloalkylphthalates, diaryl phthalates and mixed alkyl-aryl phthalates asrepresented by dimethyl phthalate, dipropyl phthalate,di(2-ethylhexyl)-phthalate, di-isopropyl phthalate, diamyl phthalate anddicapryl phthalate; alkyl and aryl phosphates such as tributylphosphate, trioctyl phosphate, tricresyl phosphate, trioctyl phosphate,tricresyl phosphate and triphenyl phosphate; alkyl citrate and citrateesters such as tributyl citrate, triethyl citrate, and acetyl triethylcitrate; alkyl adipates such as dioctyl adipate, diethyl adipate anddi(2-methoxyethyl)-adipate; dialkyl tartrates such as diethyl tartrateand dibutyl tartrate; alkyl sebacates such as diethyl sebacate, dipropylsebacate and dinonyl sebacate; alkyl succinates such as diethylsuccinate and dibutyl succinate; alkyl glycolates, alkyl glycerolates,glycol esters and glycerol esters such as glycerol diacetate, glyceroltriacetate, glycerol monolactate diacetate, methyl phythayl ethylglycolate, cutyl phthalyl butyl glycolate, ethylene glycol diacetate,ethylene glycol dibutyrate, triethylene glycol diacetate, triethyleneglycol dibutyrate and triethylene glycol dipropionate. Otherplasticizers include camphor, N-ethyl-(o- and p-toluene) sulfonamide,chlorinated biphenyl, benzophenone, N-cyclohexyl-p-toluene sulfonamide,and substituted epoxides.

Suitable plasticizers can be selected for blending with the laminaforming materials by selecting plasticizers that have a high degree ofsolvent power for the materials, are compatible with the materials overboth the processing and use temperature range, exhibit permanence asseen by a strong tendency to remain in the plasticized lamina, impartflexibility to the lamina, and are non-toxic to animals, humans, avians,fishes and reptiles. Procedures for selecting a plasticizer having thedescribed characteristics are disclosed in the Encyclopedia of PolymerScience and Technology, Vol. 10, pages 228 to 306, 1969, published byJohn Wiley & Sons, Inc. Also, a detailed description pertaining to themeasurement of plasticizer properties, including solvent parameters andcompatibility, the Hildebrand solubility parameter δ, the Flory-Hugginsinteraction parameter μ, and the cohesive-energy density, CED, parameteris disclosed in Plasticization and Plasticizer Processes, Advances inChemistry Series 48, Chapter 1, pages 1 to 26, 1965, published by theAmerican Chemical Society. The amount of plasticizer added generally isan amount sufficient to produce the desired lamina and it will varyaccordng to the plasticizer and the materials. Usually about 0.001 partup to 50 parts, or higher, of plasticizer can be used for 100 parts oflamina forming material with a presently preferred range of 0.1 part to20 parts of plasticizer, or mixtures thereof for 100 parts of laminaforming materials.

Dispersants useful for the present purpose are those dispersants whenadded to a lamina forming material and other materials aid in producingan integral composite that is useful for making the operative laminatedwall of a system. The dispersants act by regulating the surface energyof materials to improve their blending into the composite. This lattermaterial is used for manufacturing devices that maintain their integrityin the environment of use during the agent release period. Generally,the dispersants are amphipathic molecules comprised of a hydrophobicpart and a hydrophilic part. The dispersants can be anionic, cationic,nonionic or amphoteric and they include anionics such as sulfatedesters, amides, alcohols, ethers and carboxylic acids; sulfonatedaromatic hydrocarbons, aliphatic hydrocarbons, esters and ethers;acylated amino acids and peptides; and metal alkyl phosphates; cationicdispersants such as primary, secondary, tertiary and quaternaryalkylammonium salts; acylated polyamines; and salts of heterocyclicamines, arylammonium dispersants such as esters of polyhydric alcohols;alkoxylated amines; polyoxyalkylene; esters and ethers ofpolyoxyalkylene glycols; alkanolamine fatty acid condensates; tertiaryacetylamic glycols; and dialkyl polyoxyalkylene phosphates; andampholytics such as betamines; and amino acids.

Typical dispersants include polyoxyethylenated glycerol ricinoleate;polyoxyethylenated castor oil having from 9 to 52 moles of ethyleneoxide; glycerol mannitan laurate, and glycerol(sorbitan oleates,stearates or laurates); polyoxyethylenated sorbitan laurate, palmitate,stearate, oleate or hexaolate having from 5 to 20 moles of ethyleneoxide; mono-, di- and poly-ethylene glycol stearates, laurates, oleates,myristates, behenates or ricinoleates; propylene glycol carboxylic acidesters; sorbitan laurate, palmitate, oleate, and stearate;polyoxyethylenated octyl, nonyl, decyl, and dodecylphenols having 1 to100 moles of ethylene oxide; polyoxyethylenated nonyl, lauryl, decyl,cetyl, oleyl and stearyl alcohols having from 3 to 50 moles of ethyleneoxide; polyoxypropylene gylcols having from 3 to 300 moles of ethyleneoxide; sodium salt of sulfated propyl oleate; sodiumdi(heptyl)sulfosuccinate; potassium xylenesulfonate; 1:1 myristic aciddiethanolamide; N-coco-β-aminopropionic acid;bis-(2-hydroxyethyl)tallowamine oxide;(diisobutylphenoxyethoxyethyl)dimethylbenzylammonium halide;N,N'-polyoxypropylenated ethylenediamine having a molecular weight from500 to 3000; tetraalkylammonium salts with up to 26 carbon atoms in thecation; sodium or potassium salt of polypeptide cocoanut, oleic orundecylenic acid condensate; metal salts of N-acylated short chainaminosulfonic acids; soybean phosphatides; and sulfobetaine.

Suitale dispersants can be selected from the above and from otherdispersants for blending with laminae forming materials by using thedispersant's hydrophile-lipophile balance number, HLB. This numberrepresents the proportion between the weight percentages of hydrophilicand lipophilic groups in a dispersant. In use, the number indicates thebehavior of the dispersant, that is, the higher the number the morehydrophilic the dispersant and the lower the number the more lipophilicthe dispersant. The required HLB number for blending lamina formingmaterials is determined by selecting a dispersant with a known number,blending it with the materials and observing the results. A homogeneouscomposite is formed with the correct number; while a heterogenousmixture indicates a different number is needed. This new number can beselected by using the prior number as a guide. The HLB number is knownto the art for many dispersants, and they can be experimentallydetermined according to the procedure in J. Soc. Cosmetic Chem., Vol. 1,pages 311 to 326, 1949, or it can be calculated by using the procedurein J. Soc. Cosmetic Chem., Vol. 5, pages 249, to 256, 1954, and in Am.Perfumer Essent. Oil Rev., Vol. 65, pages 26 to 29, 1955. Typical HLBnumbers are set forth in Table 1. Generally a number of 10 or lessindicates lipophilic behavior and 10 or more indicates hydrophilicbehavior. Also, HLB numbers are algebraically additive. Thus, by using alow number with a high number, blends of dispersants can be preparedhaving numbers intermediate between the two numbers. The amount ofdispersant needed is an amount that when blended with lamina formingmaterials will form the desired composite; this will vary according tothe particular dispersant and materials that are blended to form thelamina. Generally, the amount of dispersant will range from about 0.001parts up to 40 parts, or higher, for 100 parts of lamina formingmaterial with a presently preferred range of 0.1 part to 15 parts ofdispersant or mixtures thereof, for 100 parts of lamina formingmaterial.

                  TABLE 1                                                         ______________________________________                                        DISPERSANT              HLB NUMBER                                            ______________________________________                                        Sorbitan trioleate      1.8                                                   Polyoxyethylene sorbitol beeswax                                                                      2.0                                                   Sorbitan tristearate    2.1                                                   Polyoxyethylene sorbitol hexastearate                                                                 2.6                                                   Ethylene glycol fatty acid ester                                                                      2.7                                                   Propylene glycol fatty acid ester                                                                     3.4                                                   Propylene glycol monostearate                                                                         3.4                                                   Ethylene glycol fatty acid ester                                                                      3.6                                                   Glycerol monostearate   3.8                                                   Sorbitan monooleate     4.3                                                   Propylene glycol monolaurate                                                                          4.5                                                   Diethylene glycol fatty acid ester                                                                    5.0                                                   Sorbitan monopalmitate  6.7                                                   Polyoxyethylene dioleate                                                                              7.5                                                   Polyoxypropylene mannitol dioleate                                                                    8.0                                                   Sorbitan monolaurate    8.6                                                   Polyoxyethylene lauryl ether                                                                          9.5                                                   Polyoxyethylene sorbitan monolaurate                                                                  10.0                                                  Polyoxyethylene lanolin derivative                                                                    11.0                                                  Polyoxyethylene glycol 400 monooleate                                                                 11.4                                                  Triethanolamine oleate  12.0                                                  Polyoxyethylene nonyl phenol                                                                          13.0                                                  Polyoxyethylene sorbitan monolaurate                                                                  13.3                                                  Polyoxyethylene sorbitol lanolin                                                                      14.0                                                  Polyoxyethylene stearyl alcohol                                                                       15.3                                                  Polyoxyethylene 20 cetyl ether                                                                        15.7                                                  Polyoxyethylene 40 stearate                                                                           16.9                                                  Polyoxyethylene monostearate                                                                          17.9                                                  Sodium oleate           18.0                                                  Potassium oleate        20.0                                                  ______________________________________                                    

Exemplary solvents suitable for manufacturing the laminates and laminaeinclude inert inorganic and organic solvents that do not adversely harmthe materials and the final laminated wall. The solvents broadly includemembers selected from the group consisting of aqueous solvents,alcohols, ketones, esters, ethers, aliphatic hydrocarbons, halogenatedsolvents, cycloaliphatic, aromatics, heterocyclic solvents and mixturesthereof. Typical solvents include acetone, diacetone alcohol, methanol,ethanol, isopropyl alcohol, butyl alcohol, methyl acetate, ethylacetate, isopropyl acetate, n-butyl acetate, methyl isobutyl ketone,methyl propyl ketone, n-hexane, n-heptane, ethylene glycol monoethylether, ethylene glycol monoethyl acetate, methylene dichloride, ethylenedichloride, propylene dichloride, carbon tetrachloride, nitroethane,nitropropane, tetrachloroethane, ethyl ether, isopropyl ether,cyclohexane, cyclooctane, benzene, toluene, naphtha, 1,4-dioxane,tetrahydrofuran, diglyme, water, and mixtures thereof such as acetoneand water, acetone and methanol, acetone and ethyl alcohol, methylenedichloride and methanol, and ethylene dichloride and methanol.

The expression "passageway" as used herein comprises means and methodssuitable for releasing the agent from the device. The expressionincludes an aperture, orifice or bore through the laminated wall formedby mechanical procedures or by eroding an erodible element, such as agelatin plug, in the environment of use. A detailed description ofosmotic passageways and the maximum and mimimum dimensions for apassageway are disclosed in U.S. Pat. Nos. 3,845,770 and 3,916,899.

The osmotically effective compounds that can be used for the purpose ofthe invention include inorganic and organic compounds that exhibit anosmotic pressure gradient against an external fluid across the laminatedwall of the system. The compounds are used mixed with an agent that haslimited solubility in the external fluid with the compounds forming asaturated solution containing agent that is osmotically delivered fromthe system. The phrase "limited solubility" as used herein means theagent has a solubility of about less than 1% by weight in the externalfluid. The compounds are used by homogeneously or heterogenously mixingthe compound or a mixture of compounds with an agent, either before theyare charged into the reservoir, or by self-mixing after they are chargedinto the reservoir. In operation, these compounds attract fluid into thesystem producing a solution of compound which is delivered from thesystem concomitantly transporting undissolved and dissolved agent to theexterior of the system. Osmotically effective compounds useful for thepresent purpose include magnesium sulfate, magnesium chloride, sodiumchloride, lithium chloride, potassium sulfate, sodium carbonate, sodiumsulfite, lithium sulfate potassium chloride, calcium bicarbonate, sodiumsulfate, calcium sulfate, potassium acid phosphate, calcium lactate,dmannitol, urea, inositol, magnesium succinate, tartaric acid,carbohydrates such as raffinose, sucrose, glucose, α-d-lactosemonohydrate, and mixtures thereof. The compound is initially present inexcess and it can be in any physical form such as particle, crystal,pellet, tablet, strip, film or granule. The osmotic pressure ofsaturated solutions of various osmotically effective compounds and formixtures of compounds at 37° C, in water, is listed in Table 2. In thetable, the osmotic pressure π, is in atmospheres, ATM. The osmoticpressure is measured in a commercially available osmometer that measuresthe vapor pressure difference between pure water and the solution to beanalyzed, and according to standard thermodynamic principles, the vaporpressure ratio is converted into osmotic pressure difference. In Table2, osmotic pressures of from 20 ATM to 500 ATM are set forth; of course,the invention includes the use of lower osmotic pressures from zero, andhigher osmotic pressures than those set forth by way of example in Table2. The osmometer used for the present measurements is identified asModel 302B, Vapor Pressure Osmometer, manufactured by the HewlettPackard Co., Avondale, Penna.

                  TABLE 2                                                         ______________________________________                                        COMPOUND OR            OSMOTIC PRESSURE                                        MIXTURE               ATM                                                    ______________________________________                                        Lactose-Fructose       500                                                    Dextrose-Fructose      450                                                    Sucrose-Fructose       430                                                    Mannitol-Fructose      415                                                    Sodium Chloride        356                                                    Fructose               355                                                    Lactose-Sucrose        250                                                    Potassium Chloride     245                                                    Lactose-Dextrose       225                                                    Mannitol-Dextrose      225                                                    Dextrose-Sucrose       190                                                    Mannitol-Sucrose       170                                                    Sucrose                150                                                    Mannitol-Lactose       130                                                    Dextrose                82                                                    Potassium Sulfate       39                                                    Mannitol                38                                                    Sodium Phosphate Tribasic . 12H.sub.2 O                                                               36                                                    Sodium Phosphate Dibasic . 7H.sub.2 O                                                                 31                                                    Sodium Phosphate Dibasic . 12H.sub.2 O                                                                31                                                    Sodium Phosphate Dibasic Anhydrous                                                                    29                                                    Sodium Phosphate Monobasic . H.sub.2 O                                                                28                                                    ______________________________________                                    

The expression "active agent" as used herein broadly includes anycompound, composition of matter or mixture thereof, that can bedelivered from the system to produce a beneficial and useful result. Theagent can be soluble in a fluid that enters the reservoir and functionsas an osmotically effective solute or it can have limited solubility inthe fluid and be mixed with an osmotically effective compound soluble influid that is delivered from the system. The active agent includespesticides, herbicides, germicides, biocides, algicides, rodenticides,fungicides, insecticides, anti-oxidants, plant growth promoters, plantgrowth inhibitors, preservatives, disinfectants, sterilization agents,catalysts, chemical reactants, fermentation agents, foods, foodsupplements, nutrients, cosmetics, drugs, vitamins, sex sterilants,fertility inhibitors, fertility promoters, air purifiers, micro-organismattenuators, and other agents that benefit the environment of use.

In the specification and the accompanying claims, the term "drug"includes any physiologically or pharmacologically active substance thatproduces a localized or systemic effect or effects in animals, includingmammals, humans and primates, avians, domestic household, sport or farmanimals such as sheep, goats, cattle, horses and pigs, for administeringto laboratory animals such as mice, rats and guinea pigs, and to fishes,reptiles and zoo animals. The active drug that can be delivered includesinorganic and organic compounds without limitation, those materials thatact on the central nervous system such as hypnotics and sedatives,including pentobarbital sodium, phenobarbital, secobarbital, thiopentaland mixtures thereof, heterocyclic hypnotics such as dioxopiperidinesand glutarimides, hypnotics and sedatives such as amides and ureas,exemplified by diethylisovaleramide and α-bromoisovaleryl urea, hypnoticand sedative urethanes and disulfanes, psychic energizers such asisocarboxazid, nialamide, phenelzine, imipramine, tranylcypromine andparglylene, tranquilizers such as chloropromazine, promazine,fluphenazine, reserpine, deserpidine, meprobamate, benzodiazepines suchas chlordiazepoxide, anticonvulsants such as primidone, enitabas,diphenylhydantoin, ethltion, pheneturide and ethosuximide, musclerelaxants and antiparkinson agents such as mephenesin, methocarbomal,trihexylphenidyl, biperiden, levo-dopa also known as L-dopa andL-β-3-4-dihydroxypehnylalanine, analgesics such as morphone, codeine,meperidine, nalorphine, antipyretics and anti-inflammtory agents suchasaspirin, salicylamide, colchicine and sodium salicylamide, localanesthetics such as procaine, lidocaine, naepaine, piperocaine,tetracaine and dibucane, antispasmodics and muscle contractants such asatropine, scopolamine, methscopolamine, oxyphenonium, papaverine,prostaglandins such as PGE₁, PGE₂, PGF₁.sub.α_(') PGF₂.sub.α and PGA,anti-microbials such as penicillin, tetracycline, oxytetracycline,chlorotetracycline, chloramphenicol and sulfonamides, anti-malarialssuch as 4-aminoquinolines, 8-aminoquinolines and pyrimethamine, hormonalagents such as prednisolone, cortisone, cortisol and triamcinolone,androgenic steroids such as methyltestosterone, and fluoxmesterone,estrogenic steroids such as 17β-estradiol, α-estradiol, estriol,α-estradiol 3-benzoate, and 17-ethynyl estradiol-3-methyl ether,progestational steroids such as progesterone, 19-nor-pregn-4-ene3,20-dione, 17-hydroxy-19-nor-17-α-pregn-5(100-ene-20-yn-3-one,17α-ethynyl-17-hydroxy-5(10)-esrtren-3-one, and9β,10α-pregna-4,6-diene-3,20-dione, sypathomimetic drugs such asepinephrine, amphetamine, ephedrine and norepinephrine, cardiovasculardrugs such as procainamide, procainamide hydrochloride, amyl nitrile,nitrogkycerin, dipyredamole, sodium nitrate and mannitol nitrate,diuretics such as chlorathiazide, acetazolamide, methazolamide andflumethiazide, antisparasitics such as bephenium, hydroxynaphthoate,dichlorophen and dapsone, neoplastics such as mechlorethamine, uracilmustard, 5-fluorouracil, 6-thioguanine and procarbazine, hypoglycemicdrugs such as insulin, isophane insulin, protamine zinc insulinsuspension, globin zinc insulin, extended insulin zinc suspension,tolbutamide, acetohexamide, tolazamide and chloropropamide, nutritionalagents such as ascorbic acid, niacin, nicotinamide, folic acid, choline,biotin, pantothenic acid, and vitamin B₁₂, essential amino acids,essential fats, eye drugs such as pilocarpine, pilocarpine salts such aspilocarpine nitrate, pilocarpine hydrochloride, dichlorphenamide,atropine, atropine sulfate, scopolamine and eserine salicylate, andelectrolytes such as calcium gluconate, calcium lactatem potassiumchloride, potassium sulfate, sodium chloride, potassium fluoride, sodiumfluoride, ferrous lactate, ferrous glucconate, ferrous sulfate, ferrousfumurate and sodium lactate. The beneficial drugs are known to the artin Remington's Pharmaceutical Sciences, 14th Ed., 1970, published byMack Publishing Co., Eston, Penna.; and in The Pharmacological Basis ofTherapeutics, by Goodman and Gilman, 4th Ed., 1970, published by theMacMillian Company, London.

The drug can also be in various forms, such as uncharged molecules,molecular complexes, pharmacologically acceptable salts such ashydrochlorides, hydrobromides, sulfate, laurylate, palmitate, phosphate,nitrate, boratem acetate, maleate, tartrate, oleate, and salicylate. Foracidic drugs, salts of metals, amines or organic cations, for examplequaternary ammonium can be used. Derivatives of drugs such as esters,ethers and amides which have solubility characteristics suitable for useherein can be used alone or mixed with other drugs. Also, a drug that iswater insoluble can be used in a form that is a water soluble derivativethereof to effectively serve as a solute, and on its release from thedevice, is converted by enzymes, hydrolyzed by body pH or othermetabolic processes to the original form, or to a biologically activeform. The agent can be in the reservoir as a solution, dispersion,paste, cream, particle, granule, emulsion, suspension or powder. Also,the agent can be mixed with a binder, dispersant, emulsifier or wettingagent and dyes.

The amount of agent present in the system is initially in excess of theamount that can be dissolved in the fluid that enters the reservoir.Under this physical state when the agent is in excess, the system willosmotically operate to give a substantially constant rate of release.The rate of agent release pattern can also be varied by having differentamounts of agent in the reservoir to form solutions containing differentconcentrations of agent for delivery from the device. Generally, thesystem can house from 0.05 ng to 5 grams or more, with individualsystems containing for example, 25 ng, 1 mg, 5 mg, 250 mg, 1.5 g, andthe like.

The solubility of an agent in an external fluid can be determined byvarious art known techniques. One method consists in preparing asaturated solution comprising the external fluid plus the agent asascertained by analyzing the amount of agent present in a definitequantity of the fluid. A simple apparatus for this purpose consists of a

test tube of medium size fastened upright in a water bath maintained atconstant temperature and pressure, for example, one atmosphere, in whichthe fluid and agent are placed and stirred by a motor driven rotatingglass spiral. After a given period of stirring, a definite weight of thefluid is analyzed and the stirring continued for an additional period oftime. If the anaylsis shows no increase of dissolved agent aftersuccessive periods of stirring, in the presence of excess solid agent inthe fluid, the solution is saturated and the results are taken as thesolubility of the product in the fluid. If the agent is soluble, anadded osmotically effective compound optionally may not be needed; ifthe agent has limited solubility in the fluid, then an osmoticallyeffective compound can be incorporated into the device. Numerous othermethods are available for the determination of the solubility of anagent in a fluid. Typical methods used for the measurement of solubilityare chemical analysis, ultra violet spectometry, density, refractiveindex and electrical conductivity. Details of various methods fordetermining solubilities are described in United States Public HealthService Bulletin, No. 67 of the Hygienic Laboratory; Encyclopedia ofScience and Technology, Vol, 12, pages 542 to 556, 1971, published byMcGraw-Hill, Inc.; and Encyclopaedic Dictionary of Physics, Vol. 6,pages 547 to 557, 1962, published by Pergamon Press, Inc.

The systems of the invention are manufactured by standard techniques.For example, in one embodiment, the agent and other ingredients that maybe housed in the compartment and a solvent are mixed into a solid,semisolid or gel form by conventional methods such as ballmilling,calendering, stirring, or rollmilling and then pressed into apreselected shape. The laminae forming devices system can be applied bymolding, spraying or dipping the pressed shape into wall formingmaterials. In another embodiment, the laminae can be cast into films,shaped to the desired dimensions, an exterior lamina sealed to aninterior lamina to define a compartment that is filled with agent andthen closed. The system also can be manufactured with an emptycompartment that is filled through the passageway. The system whenformed of more than one laminate, joined by various joining techniquessuch as high frequency electronic sealing that provides clean edges andfirmly sealed systems. Another, and presently preferred, technique thatcan be used to apply lamina to a compartment is the air suspensionprocedure. This procedure consists in suspending and tumbling thepressed agent in a current of air and a lamina composition until thelamina is applied to the agent. The procedure is repeated with adifferent lamina to form the laminate. The air suspension procedure isdescribed in U.S. Pat. No. 2,799,241; J. Am. Pharm. Assoc., Vol. 48,pages 451 to 459, 1959; and ibid, Vol. 49, pages 82 to 84, 1960. Otherstandards manufacturing procedures are described in Modern PlasticsEncyclopedia, Vol. 46, pages 62 to 70, 1969; and in PharmaceuticalSciences, by Remington, Fourteenth Edition, pages 1626 to 1678, 1970,published by Mack Publishing Company, Easton, Penna.

The following examples are merely illustrative of the present invention,and they should not be considered as limiting the scope of the inventionin any way, as these examples and other equivalents thereof will becomeapparent to those versed in the art in the light of the presentdisclosure, the drawings and the accompanying claims.

EXAMPLE 1

An osmotic therapeutic system for delivering ascorbic acid at anosmotically controlled rate was manufactured as follows: first, 200grams of ascorbic acid was slowly added to 10 grams of ethylcellulose in100 milliliters of isopropyl alcohol and the material blended for 45minutes to produce wet granules. The granules were dried at 50° C for 48hours and then passed through a No. 20 mesh sieve. Then, the granuleswere lubricated with 1% magnesium stearate by mixing in a blender andafter 30 minutes of blending they were passed through a No. 20 sieve.The granules were then pressed into a solid mass using a standardtableting machine and a 3/8 inch diameter punch. The compressed mass hada finished hardness of 7.1 kg as measured by a Strong-Cobb hardnesstester. Each mass contained 450 mg of ascorbic acid, and had a totalarea of 2.6 cm².

Next, a lamina forming composition identified as h₁ was prepared bythoroughly blending in a high shear blender for 50 minutes a batchcomprising 29% cellulose acetate having an acetyl content of 38.3%, 61%cellulose acetate having an acetyl content of 32%, and 10% polyethyleneglycol having a molecular weight of 400 dissolved in an acetone:watersolvent formulation having a 90:10 weight-to-weight ratio to produce ahomogeneous composite.

Then, the compressed mass were placed in a Wurster air suspensionmachine and each mass coated with lamina h₁ until it had a lamina 3 milsthick. The vlaue for kπ₁ was 0.14 cm³.mil/cm². hr.

A second lamina forming composition, identified as h₂ was prepared bythoroughly blending in a high shear blender the following constituents:90% cellulose acetate having an acetyl content of 32%, and 10%polyethylene glycol having a molecular weight of 400 dissolved in a 90parts acetone to 10 parts water solvent, weight-to-weight, for 50minutes to produce a 5% polymeric composite.

Next, the total exposed surface of lamina h₁ distant from the ascorbicacid was laminated in the Wurster machine with lamina forming compositeh₂ until lamina h₂ had a thickness of 2 mils. The flux transmission, kπ₂was 0.22 cm³. mil/cm².hr. The resulting laminated wall, comprised oflaminae h₁ and h₂, had a thickness, h_(t), of 5 mils and a kπ_(t) of0.16 cm³. mil/cm².hr. An osmotic passageway was drilled through thelaminated wall for releasing ascorbic acid from the compartment. Thepassageway had a diameter of 10 mils and the device had a rate ofrelease of 30 mg per hour.

EXAMPLE 2

A plurality of osmotic drug delivery systems are manufactured accordingto the procedure of Example 1 wherein the conditions were as describedexcept that the drug of Example 1 is replaced with an orallyadministrable drug selected from the group consisting of methazolamide,ethoxyolamide, diazepan, amitriptylene hydrochloride, imipraminehydrochloride, naicin, benzthiazide, chorothiazide, tolbutamide,tolazamide, chloropropamide, procainamide hydrochloride, colchicine, andatropine.

EXAMPLE 3

A plurality of osmotic drug delivery systems are manufactured accordingto the procedures of Examples 1 and 2 with all conditions as describedexcept that lamina h₁ was replaced with a lamina selected from the groupof laminae consisting of cellulose acetate propionate, cellulose acetatebutyrate, cellulose acetate benzoate and cellulose acetateethylcarbamate.

EXAMPLE 4

An osmotic therapeutic system manufactured in the form of an oral,osmotic device for releasing the lysine salt of acetylsalicylic acid inthe gastrointestinal tract was made as follows: first, 450 mg of thesalt was compressed by a standard technique with a 3/8 inch punch into acompressed mass having a total area of 2.9 cm². The mass was thensurrounded with a laminated wall comprised of inner and outer laminae.

The inner lamina was a composite formed of a blend of 90% nonerodible,inert cellulose acetate having an acetyl content of 39.8%, and 10%polyethylene glycol having a molecular weight of 400. This blend wasdissolved in acetone to form a 5% solution, by weight. The compressedmass of lysine salt was then coated with the celluloseacetate/polyethylene glycol blend according to the air suspensiontechnique described in J. Pharm. Sci., Vol. 53, No. 8, pages 877 to 881,1964, and ibid, Vol. 53, No. 8, pages 953 to 955, 1964. The dried innerlamina had a thickness h₁ of 0.5 mils and a kπ₁ of 0.03 cm³.mils/cm².hr.

Next, an outer lamina that maintains its integrity in the environment ofuse, and consisting of polymeric cellulose acetate having an acetylcontent of 32% was laminated onto the exposed surface of lamina h₁ toform an integral laminated wall that surrounded the drug compartment.The cellulose acetate was intimately laminated to lamina h₁ from a blendconsisting of 90% cellulose acetate having an acetyl content of 32% and10% polyethylene glycol having a molecular weight of 400 inacetone:water in the proportion of 88.5:11.5, weight-to-weight. Theouter lamina h₂ had a thickness of 4.0 mils and a kπ₂ of 0.19cm³.mils/cm².hr.

The laminated wall, h_(t), of the system had a thickness of 4.5 mils. Anosmotic passageway was drilled through the wall and it had a diameter of9 mils. The system had a controlled and continuous rate of release of 40mg/hr with a variation of about ± 3 to 5% over a prolonged period oftime.

EXAMPLE 5

A plurality of osmotic drug delivery systems are manufactured accordingto the procedure of Example 4 with all conditions as described exceptthe lamina forming material in h₁ is replaced with a member selectedfrom the group consisting of cellulose propionate having a propionylcontent of 38.5%, cellulose acetate propionate having an acetyl contentof 1.5 to 7% and a propionyl content of 39 to 42%, and cellulose acetatebutyrate having an acetyl content of 13 to 15% and a butyryl content of34 to 39%.

EXAMPLE 6

The procedure of Example 4 is repeated in this example with allconditions as previously described except that lamina h₂ in this exampleis a semipermeable homopolymer comprising 100% cellulose acetate havingan acetyl content of 32%.

EXAMPLE 7

The procedure of Example 4 is repeated in this example and allconditions are as described except the system is sized, shaped andadapted as an ocular therapeutic system and the drug in the compartmentis replaced with an ophthalmic drug that is a member selected from thegroup consisting of idoxuridine, phenylephrine, pilocarpinehydrochloride, eserine, carbachol, phospholine iodine, demecariumbromide, cyclopentolate, homatropine, scopolamine and epinephrine.

EXAMPLE 8

An oral, osmotic system for releasing theophylline monoethanolamine overa six to seven hour therapeutic period is manufactured as follows:first, a multiplicity of compressed drug cores are formed in aconventional Manesty tableting machine for lamination. The machine usesa 5/16 inch diameter concave punch to produce compressed cores having ahardness of about 8.42 kg as measured by a Strong-Cobb hardness tester.The cores have an area of about 1.63 cm². The cores contained 125 mgs oftheophylline, present as the monoethanolamine, 8.74 mgs of binderpolyvinylpyrrolidone and 1.58 mgs of lubricant magnesium stearate. Thecones were placed in a Wurster air suspension machine that air tumbledthe cores until they are uniformly coated with a laminated wall. Thelaminated wall has an inner lamina facing the drug compartment and anouter lamina distant from the compartment.

The laminae are consecutively coated with the Wurster machine to form anintegral, laminated wall. The inner lamina is coated from a blend madeby adding (1) a mixture of 68.1% cellulose acetate having an acetylcontent of 38.3% and 12.76% polyethylene glycol having a molecularweight of 400 dissolved in a solvent consisting of 80 parts of methylenechloride and 20 parts of methanol, to (2) a mixture of 17.02%hydroxybutyl methylcellulose and 2.12% polyoxypropylene glycol having amolecular weight of 950 dissolved in 80 parts of methylene chloride and20 parts of methanol. The two mixtures were thoroughly blended and thenan additional solvent was added that consisted of 90 parts of acetoneand 10 parts of water. All the materials were stirred for 30 minutes.The inner lamina h₁ had a thickness of 0.5 mils and a kπ₁ of 0.052cm³.mils/cm².hr.

The outer lamina was permanentlylaminated onto lamina h₁ from a blendprepared as follows: to a first mixture consisting of 76.6% celluloseacetate having an acetyl content of 32% and 12.76% polyethylene glycolhaving a molecuar weight of 400 dissolved in a solvent consisting of 80parts of methylene chloride and 20 parts of methanol were added a secondmixture with continuous stirring. The second mixture consisted of 8.51%hydroxybutyl methylcellulose and 2.12% of polyoxypropylene glycol havinga molecular weight of 950 dissolved in a solvent consisting of 80 partsof methylene chloride and 20 parts of methanol. The stirring continueduntil the two mixtures were thoroughly blended. Then, an additionalsolvent, consisting of 90 parts of acetone and 10 parts of water, wasadded to the blend and all the materials stirred for 30 minutes until ahomogeneous composite was formed. The applied laminae had a thickness h₂of 4.5 mils and a kπ₂ of 0.22 cm³.mil/cm².hr.

Finally, a 10 mil aperture was mechanically drilled through thelaminated wall to produce the osmotic system. The laminated wall had athickness h_(t) of 5 mils and a kπ_(t) of 0.166 cm³.mils/cm².hr. Thesystem had a release rate of 20 mgs/hr over a prolonged period of time.

EXAMPLE 9

The procedure of Example 8 is repeated but the drug in the compartmentis replaced with a member selected from the group consisting ofnicotinamide, mannitol hexanitrate, isocarboxyazid, trimacinolone,salicylamide, aspirin and aminophylline.

EXAMPLE 10

An osmotic, therapeutic system for the controlled and continuous oralrelease of the beneficial agent sodium acetazolamide is made as follows:first, 170 grams of sodium acetazolamide and 8.5 grams of 5%polyvinylpyrrolidone in isopropyl alcohol are blended in a standardV-blender for 45 minutes to produce wet granules. The granules are driedin an oven at 50° C for 48 hours and passed through a standard No. 30mesh sieve. Then, 1.8 grams of magnesium stearate were separately passedthrough the No. 30 sieve and the granules were mixed with the magnesiumstearate in the blender for about 30 minutes, or until a uniform mixtureis obtained. The mixture is then compressed in a conventional Manestymachine using a 5/16 inch diameter concave punch to produce drug cores.The cores have a hardness of about 9 kg, as measured by a Strong-Cobbhardness tester. The cores contain 125 mgs of acetazolamide and have anarea of 1.4 cm².

The laminated wall is prepared as follows: first, an inner lamina, h₁,forming blend is prepared by blending 90% cellulose acetate having anacetyl content of 38.3% and 10% polyethylene glycol having a molecularweight of 400 in sufficient acetone to produce a 5% polymeric solution.

Next, an outer lamina, h₂, forming blend is prepared by blending 90%cellulose acetate having an acetyl content of 32% and 10% polyethyleneglycol having a molecular weight of 400 in sufficient solvent consistingof acetone:water in the ratio of 90:10 The materials were blended asdescribed to produce a 5% polymeric solution.

Then, the drug cores prepared as above were placed in a Wurster airsuspension machine. The cores were air tumbled until they were uniformlycoated with the inner lamina forming solution. The coated cores weredried in an oven at 50° C for one week to evaporate the solvent. Next,the dried cores are returned to the Wurster machine and coated with theouter lamina forming solution. The laminated product was dried asdescribed. Finally, a 7.5 mil passageway was mechanically drilledthrough the laminated wall.

The inner lamina h₁ had a thickness of 1.5 mils and a kπ₁ of 0.103cm³.mil/cm².hr. The outer lamina h₂ had a thickness of 4 mils and a kπ₂of 0.38 cm³.mils/cm².hr. The laminated h_(t) had a thickness of 5.5 milsand a kπ_(t) of 0.21 cm³.mil/cm².hr. The system had a controlled andcontinuous rate of release of about 20 mgs per hour over a prolongedperiod of time.

EXAMPLE 11

The procedure of Example 10 is repeated with all lamination proceduresas described, but the drug in the compartment is replaced with a memberselected from the group consisting of calcium gluconate, calciumlactate, potassium sulfate, potassium fluoride, sodium fluoride, ferrouslactate, ferrous gluconate, ferrous sulfate, ferrous fumurate, andsodium lactate, which drugs are released in an effective amount at acontrolled and continuous rate over a prolonged period of time.

EXAMPLE 12

An osmotic therapeutic system for releasing sodium fluoride at anosmotically controlled rate was made as follows: first, 26.6 grams ofsodium fluoride, consisting of cubic and tetragonal crystals, were mixedwith 173.4 grams of mannitol to produce 200 grams of a homogeneousdispersion. Then, 170 grams of the dispersion and 8.5 grams of 5%polyvinylpyrrolidone in isopropyl alcohol were blended in a standardV-blender for 45 minutes to produce wet granules. The granules weredried in an oven at 50° C for 48 hours and passed through a standard No.30 mesh sieve. Then, 2.0 grams of magnesium stearate were passed throughthe No. 30 sieve and the granules mixed with the magnesium stearate inthe blender for about 30 minutes. The mixture was then added to aManesty machine and drug cores pressed using a 0.375 inch diameterconcave punch to produce compressed drug cores. The cores have ahardness of about 8.5 kg as measured by the Strong-Cobb hardness tester.Each compressed mass had an area of 2.12 cm² and weighed 305 mgs. Eachmass was then surrounded with a laminated wall as follows: first, aninner lamina h₁ was prepared by blending 170 grams of cellulose acetatehaving an acetyl content of 32% with 30 grams of polyethylene glycolhaving a molecular weight of 400 in sufficient solvent consisting ofacetone:water in the ratio of 90:10 weight-to-weight and thematerialsblended to produce 5% lamina forming solution.

Next, an outer lamina h₂ forming blend was prepared by blending 170grams of cellulose acetate having an acetyl content of 38.3% and 30grams of polyethylene glycol having a molecular weight of 400 in acetoneand the material blended as described to produce a 5% polymericsolution.

Next, the cores were placed in a Wurster air suspension machine and airtumbled until the cores were uniformly coated with the inner laminaforming solution. The coated cores were dried in an oven at 50° C forone week to evaporate the solvent. The, the dried cores were returned tothe machine, and the cores again tumbled until they were coateduniformly with the outer lamina forming solution, h₂, was permanentlylaminated thereto to form laminated wall h_(t). The laminated productwas dried as described. Finally, an 8 mil aperture was drilled throughthe laminated wall.

The inner lamina h₁ had a thickness of 3 mils and a kπ₁ of 0.25cm³.mils/cm².hr. The outer lamina h₂ had a thickness of 1 mil and a kπ₂of 0.05 cm³.mil/cm².hr. lThe laminated wall had a thickness of 4 milsand a kπ_(t) of 0.125 cm³.mils/cm².hr. The system had a controlled andcontinuous rate of release of 2.5 mgs/hr of sodium fluoride over aprolonged period of time.

EXAMPLE 13

An osmotic therapeutic system manufactured in the form of an oral,osmotic device for releasing potassium chloride in the gastrointestinaltract was made as follows: first, 500 mgs cores of potassium chloridewere compressed by standard techniques with a 0.375 inch punch into asolid mass having an area of 2.3 cm². Each mass was then surrounded witha laminated wall comprised of an inner and outer laminae. The innerlamina was formed of non-erodible, inert, 70 minutes hydrolyzedsemipermeable polyvinyl acetate applied by the air suspension techniquesdescribed in J. Pharm. Sci., Vol. 53, No. 8, pages 877 to 881, 1964, andibid, Vol. 53, No. 8, pages 953 to 955, 1964. A 5% polymer solution inethanol:water in the ratio of 95:5 volume-to-volume was used to form thelamina. The lamina h₁ had a thickness of 2 mils and a kπ₁ of 0.1cm³.mil/cm².hr.

Next, an outer lamina h₂ forming blend was prepared by blending 270grams of cellulose acetate having an acetyl content of 32% and 30 gramsof polyethylene glycol having a molecular weight of 400 in sufficientsolvent consisting of acetone:water and in the ratio of 90:10weight-to-weight and the materials blended to produce a 5% solution.

Then, the outer lamina h₂ was laminated onto lamina h₁ accoridng to theprocedure described in Example 12. Lamina h₂ has a thickness of 3 milsand a kπ₂ of 0.54 cm³. mil/cm². hr. A 9 mil apert ure was drilledthrough the laminated wall. The laminated wall h_(t) had a thickness of5 mils and a kπ_(t) of 0.195 cm³. mils/cm². hr. The system had a rate ofrelease of 30 mgs per hour.

EXAMPLE 14

An osmotic therapeutic system for delivering NaCl at an osmoticallycontrolled rate was manufactured according to the procedures of Examples1, 10 and 12 with all conditions as described, except that the laminatedwall surrounding the compartment comprised three laminae in laminararrangement. The lamina facing the drug compartment, h₁ consists ofsemipermeable 90 minutes partially hydrolyzed polyvinyl acetate. Thelamina had a thickness of 2 mils and a kπ₁ of 0.3 cm³. mil/cm². hr. Thesecond lamina h₂ was laminated to lamina h₁ and it consists of 40%cellulose acetate having an acetyl content of 38.3%, 40% celluloseacetate having an acetyle content of 32%, and 20% polyethylene glycolhaving a molecular weight of 400. Lamina h₂ had a thickness of 2 milsand a kπ₂ of 0.46 cm³. mil/cm². hr. The third lamina h₃ distant from thecompartment, consists of 90% cellulose acetate having an acetyl contentof 32% and 10% polyethylene glycol 400. Lamina h₃ had a thickness of 1mil and a kπ₃ of 0.5 cm³.mil/cm². hr. The laminated wall h_(t) comprisedof h₁ + h₂ + h₃, had a thickness of 5 mils and a kπ_(t) of 0.385 cm³.mil/cm². hr. A 10 mil aperture through h_(t) released NaCl at the rateof 55 mgs/hr, with a variation of ± 5% over a prolonged period of time.

EXAMPLE 15

An osmotic ocular therapeutic system for the delivery of pilocarpinenitrate at a rate of 103 μg/hr from a system having a laminated wallwith a total area of 1.2 cm² and a thickness of 3 mils, with thepilocarpine nitrate having a solubility of 250 mg/ml in water, anddesigned in the form of an elliptical shaped device is constructed asfollows: to a drug core of pilocarpine nitrate is applied from dimethylformamide, a 1 mil thick h₁ lamina of inert semipermeable poly(urethane)to yield an inner lamina having a lπ₁ of 0.36 × ;10⁻ ³ cm³. mil/cm². hr.Next, to the total outer surface of h₁ is applied from a 5% solution inacetone: water, in the ratio of 90:10 weight-to-weight a 2 mil thick h₂lamina of semipermeable inert blend of 50% cellulose acetate having anacetyl content of 32% and 50% cellulose acetate having an acetyl contentof 38.3%. Lamina h₂ had a kπ₂ of 0.018 cm³. mil/cm². hr. The laminatedwall has an aperture of 6.9 mils. The laminated wall h_(t) has a kπ_(t)of 1 × 10⁻ ³ cm³. mil/cm². hr, and the system when placed in thecul-de-sac of an adult human eye, admisters 103 μg/hr.

EXAMPLE 16

A series of oral osmotic therapeutic systems are manufactured using theabove procedures. Each system comprises a laminated wall having a pairof laminae formed of a blend of semipermeable materials, with thelaminae facing the compartment, the inner laminae, exposed to agent,having an increased acetyl content for the series. The results obtainedindicated the inner laminae in the presence of agents KC1, NaCl, MgSO₄and K₂ SO₄ are substantially non-erodible and inert, and the laminaehave increased rejection to the passage of agent as the percent acetylcontent increases in the laminae. The measured permeability results forthis system are set forth in FIG. 7. In FIG. 7, the numbers on theabscissa represent the percent acetyl content for the laminae exposed toagents. The numbers on the left ordinate represent the permeability ofthe laminae to the passage of agents. Also, the letter x indicates thelamina was exposed to KCl, a triangle indicates the lamina was exposedto NaCl, the squares indicate the lamina was exposed to MgSO₄ and thecircle indicates the lamina was exposed to K₂ SO₄.

The novel osmotic devices of this invention use means for the obtainmentof precise release rates in the environment of use while simultaneouslymaintaining the integrity of the device. While there has been describedand pointed out features of the invention as applied to presentlypreferred embodiments, those skilled in the art will appreciate thatvarious modifications, changes, additions, and omissions in the devicesillustrated and described can be made without departing from the spiritof the invention.

What is claimed is:
 1. An osmotic system for dispensing an active agentto an environment of use, said system comprising:a. a shaped wallcomprising a pair of laminae comprising an exterior lamina consisting ofa multiplicity of materials blended to form a lamina that is permeableto the passage of an external fluid and maintains its physical andchemical integrity in the environment of use, and an interior laminaconsisting of a multiplicity of materials blended to form a lamina thatis permeable to the passage of an external fluid, substantiallyimpermeable to the passage of agent and maintains its physical andchemical integrity in the presence of agent, said wall surrounding, withthe interior lamina facing; b. a compartment containing an active agentthat is soluble in the fluid and exhibits an osmotic pressure gradientacross the wall against the fluid; c. a compartment in the wallcommunicating with the compartment and the exterior of the device fordispensing agent from the device; and d. wherein in operation when thedevice is in the environment of use, fluid from the environment iscontinually inbibed through the wall into the compartment in a tendencytowards osmotic equilibrium at a rate determined by the permeability ofthe wall and the osmotic pressure gradient across the wall, therebycontinuously dissolving agent which is dispensed at a controlled andcontinuous rate over a prolonged period of time.
 2. The osmotic systemfor dispensing an agent according to claim 1 wherein the exterior laminais substantially non-erodible and inert in the environment of use. 3.The osmotic system for dispensing an agent according to claim 1 whereinthe interior lamina is substantially non-erodible and inert in thepresence of agent and solutions thereof.
 4. The osmotic system fordispensing an agent according to claim 1 wherein the laminae comprise atleast one semipermeable lamina forming material.
 5. The osmotic systemfor dispensing an agent according to claim 1 wherein the laminaecomprise a cellulose ester having a degree of substitution on itsanhydroglucose groups of greater than 0 and up to 3 inclusive.
 6. Theosmotic system for dispensing an agent according to claim 1 wherein thelaminae contain a member selected from the group consisting of celluloseacylates, cellulose diacylates, cellulose triacylates, celluloseacetate, cellulose diacetate, cellulose triacetate, cellulosepropionate, cellulose acetate propionate and cellulose acetate butyrate.7. The osmotic system for dispensing an agent according to claim 1wherein the laminae contain at least one material that imparts stabilityto the laminae.
 8. The osmotic system for dispensing an agent accordingto claim 1 wherein the system is sized, shaped and adapted as a dosageform for dispensing an agent in the gastrointestinal tract.
 9. Theosmotic system for dispensing an agent according to claim 1 wherein thepassageway is formed in the environment of use.
 10. The osmtoic systemfor dispensing an agent according to claim 1 wherein the agent is amember selected from the group consisting of locally and systemicallyacting drugs.
 11. The osmotic system for dispensing an agent accordingto claim 1 wherein the agent is a member selected from the groupconsisting of acetazolamide, methazolamide, potassium chloride, niacin,aspirin, meprobamate, salicylamide, theophylline monoethanolamine,aminophylline, procainamide hydrochloride, colchicine and atropine. 12.The osmotic system for dispensing an agent according to claim 1 whereinthe laminae contain a plasticizer.
 13. The osmotic system for dispensingan agent according to claim 1 wherein the laminae containing aplasticizer selected from the group consisting of cyclic and acyclicplasticizers.
 14. The osmotic system for dispensing an agent accordingto claim 1 wherein the laminae contain an amphipatic dispersantcomprising hydrophilic and hydrophobic groups.
 15. The osmotic systemaccording to claim 1 wherein the laminae contain a dispersant selectedfrom the group consisting of anionic, cationic, nonionic and amphotericdispersants.
 16. The osmotic system for dispersing an agent according toclaim 1 wherein the laminae contain a flux regulator that decreases orincreases the permeability of the laminae to the passage of fluid. 17.The osmotic system for dispensing an agent according to claim 1 whereinthe laminae contain a cellulose ether.
 18. The osmotic system fordispensing an agent according to claim 1 wherein the compartmentcontains an osmotically effective compound that exhibits an osmoticpressure gradient across the wall from greater than 0 up to 500atmospheres.
 19. The osmotic system for dispensing an agent according toclaim 1 wherein the system is sized, shaped and adapted for placement ina vagina.
 20. An osmotic system for the continuous dispensing of anactive agent to an environment of use comprising:a. a shaped wallcomprising an interior lamina consisting of at least two materials thatform a lamina permeable to the passage of an external fluid,substantially impermeable to the passage of agent and essentiallymantains its physical and chemical integrity in the presence of agent,said lamina in laminar arrangement with an exterior lamina formed of amaterial permeable to the passage of fluid and essentially maintains isphysical and chemical integrity in the environment of use, said wallsurrounding, with the interior lamina facing; b. a compartmentcontaining the active agent that is soluble in the external fluid andexhibits an osmotic pressure gradient across the wall against the fluid;c. a passageway in the wall communicating with the compartment and theexterior of the system for dispensing agent from the system; and, d.wherein in operation when the system is placed in the environment ofuse, fluid from the environment is imbibed through the wall into thecompartment in a tendency towards osmotic equilibrium at a ratedetermined by the permeability of the wall and the osmotic pressuregradient across the wall, thereby dissolving agent which is dispersedthrough the passageway at a controlled and continuous rate over aprolonged period of time.
 21. The osmotic system for dispensing an agentaccording to claim 20 wherein the interior lamina is formed of asemipermeable material and a stabilizing material that imparts integrityto the lamina.
 22. The osmotic system for dispensing an agent accordingto claim 20 wherein the interior lamina is formed of a semipermeablematerial, a stabilizing material and a dispersant that blends thematerials.
 23. The osmotic system for dispensing an agent according toclaim 20 wherein the interior lamina is formed of a semipermeablematerial, a stabilizing material, a dispersant, and a plasticizer. 24.The osmotic system for dispensing an agent according to claim 20 whereinthe interior lamina is formed of a semipermeable material, a stabilizingmaterial, a dispersant, a plasticizer, and a flux regulator.
 25. Theosmotic system for dispensing an agent according to claim 20 wherein theinterior lamina contains a cellulose ester having a degree ofsubstitution on its anhydroglucose groups of greater than 0 and up to 3inclusive.
 26. The osmotic system for dispensing an agent according toclaim 20 wherein the interior lamina contains a member selected from thegroup consisting of cellulose acylates, cellulose diacylates, cellulosetriacylates, cellulose acetate, cellulose diacetate, cellulosetriacetate, cellulose propionate, cellulose acetate propionate, andcellulose acetate butyrate.
 27. The osmotic system for dispensing anagent according to claim 20 wherein the interior lamina contains astabilizing material selected from the group consisting of celluloseesters having on its anhydroglucose groups a degree of substitutiongreater than 0 and up to 3 inclusive, cellulose ethers and mixturesthereof.
 28. The osmotic system for dispensing an agent according toclaim 20 wherein the interior lamina contains a semipermeable materialand a stabilizing material possessing different chemical and physicalproperties than the semipermeable material and selected from the groupconsisting of cellulose acylates, cellulose diacylates, cellulosetriacylates, cellulose acetate, cellulose diacetate, cellulosetriacetate, hydroxymethyl cellulose, hydroxypropyl methylcellulose,hydroxybutyl methylcellulose, and mixtures thereof.
 29. The osmoticsystem for dispensing an agent according to claim 20 wherein theinterior lamina contains a plasticizer selected from the groupconsisting of cyclic and acyclic plasticizers and mixtures thereof. 30.The osmotic system for dispensing an agent according to claim 20 whereinthe interior lamina contains a plasticizer selected from the groupconsisting of phthalates, phosphates, citrates, adipates, tartrates,sebacates, succinates, glycolates, glycerolates, benzoates, myristates,sulfonamides and halogenated phenyls.
 31. The osmotic system fordispensing an agent according to claim 20 wherein the interior laminacontains a dispersant selected from the group consisting of anionic,cationic, nonionic and amphoteric dispersants, and mixtures thereof. 32.The osmotic system for dispensing an agent according to claim 20 whereinthe interior lamina contains a dispersant selected from the groupconsisting of polyoxyalkylene glycol, esters of polyoxyalkylene glycols,esters of polyhydric alcohols, sulfated esters, sulfated amides,quaternary ammonium salts, alkanolamine fatty acids, tertiaryalkylamonium salts, and mixtures thereof.
 33. The osmotic system fordispensing an agent according to claim 20 wherein the system is sized,shaped and adapted for dispensing an agent in the gastrointestinaltract.
 34. The osmotic system for dispensing an agent according to claim20 wherein the agent is a member selected from the group consisting oflocally and systemically acting drugs.
 35. The osmotic system fordispensing an agent according to claim 20 wherein the soluble agent ismixed with an osmotically effective compound.
 36. The osmotic system fordispensing an agent according to claim 20 wherein the passageway isformed in the environment of use.
 37. The osmotic system for dispensingan agent according to claim 20 wherein the agent in the compartment ismixed with a member selected from the group consisting of a binder, apharmaceutically acceptable dye, a lubricant, and mixtures thereof. 38.The osmotic system for dispensing an agent according to claim 20 whereinthe agent is a member selected from the group consisting of tolbulamide,tolazamide, chloropropamide, mannitol hexanitrate, tranylcypromine,progestational steroids, and estrogenic steroids.
 39. The osmotic systemfor dispensing an agent according to claim 20 wherein the interiorlamina contains a flux regulator selected from the group consiting ofaliphatic diols, polyalkylene glycols, poly(α,ω)-alkylenediols, estersof alkylene glycols and mixtures thereof.
 40. The osmotic system fordispensing an agent according to claim 20 wherein the exterior lamina isa member selected from the group consisting of cellulose ethers,polyamides and polyurethanes.
 41. An osmotic system for the continuousdispensing of an active agent to an environment of use comprising:a. ashaped wall comprising an interior lamina formed of a semipermeablematerial that is permeable to the passage of an external fluid,substantially impermeable to the passage of agent and essentiallymaintains its physical and chemical integrity in the presence of agent,said lamina laminated to an exterior lamina formed of at least twomaterials with the lamina permeable to the passage of fluid andessentially maintains its physical and chemical integrity in theenvironment of use, said wall surrounding, with the interior laminafacing; b. a compartment containing an active agent that is soluble inthe external fluid and exhibits an osmtoic pressure gradient across thewall against the fluid; c. a passageway in the wall communicating withthe compartment and the exterior of the system for dispensing agent fromthe system; and, d. wherein in operation when the system is placed inthe environment of use, fluid from the environment is imbibed throughthe wall into the compartment in a tendency towards osmotic equilibriumat a rate determined by the osmotic pressure gradient across the wall,thereby dissolving agent which is dispensed through the passageway at acontrolled and continuous rate over a prolonged period of time.
 42. Theosmotic system for dispensing an agent according to claim 41 wherein thesemipermeable material forming the interior lamina is a polymer.
 43. Theosmotic system for dispensing an agent according to claim 41 wherein theexterior lamina comprises a semipermeable polymeric lamina formingmaterial blended with a hydrophobic stabilizing material and ahydrophilic flux regulating material.
 44. The osmotic system fordispensing an agent according to claim 41 wherein the passageway isformed in the environment of use.
 45. The osmotic system for dispensingan agent according to claim 41 wherein the exterior lamina comprises asemipermeable polymeric lamina forming material blended with aplasticizer.
 46. The osmotic system for dispensing an agent according toclaim 41 wherein the exterior lamina comprises a semipermeable polymer,a stabilizing material, a dispersant, a flux regulating material and aplasticizer that lowers the glass transition temperature of the polymer.47. The osmotic system for dispensing an agent according to claim 41wherein the agent is a drug and the system is sized, shaped and adaptedfor dispensing the drug to a receptor selected from the group consistingof eye, ear, nose, gastrointestinal ract, vagina, uterus, anus, skin,and systemic circulation drug receptor sites.
 48. The osmotic system fordispensing an agent according to claim 41 wherein the agent is a memberselected from the group consisting of idoxuridine, phenylephrine,pilocarpine, pilocarpine salts, eserine, carbachol, phospholine iodine,demecarium bromide, cyclopentolate, homatropine, scopolamine,epinephrine and mixtures thereof.
 49. An osmotic system for thecontinuous dispensing of an active agent to an environment of usecomprising:a. a shaped laminated wall comprising at least two laminaecomprising a multiplicity of materials, said laminae forming a laminatedwall that is permeable to the passage of an external fluid andsubstantially impermeable to the passage of agent with the wallsurrounding and forming; b. a compartment containing an active agent; c.a passageway in the wall communicating with the compartment and theexterior of the system for dispensing agent from the system; and, d.wherein the operation, when the system is placed in the environment ofuse, fluid from the environment is continuously imbibed through thelaminated wall, having a total thickness h_(t), into the compartment ina tendency towards osmotic equilibrium at a rate proportional to thefluid transmission rate (kπ)_(t) of the laminated wall which rate isgoverned by the following equation: ##EQU5## wherein h₁, h₂ and h_(n)are the thickness of the individual lamina, and (kπ)₁, (kπ)₂ and(kπ)_(n) are the fluid transmission rates for the respective laminae,said imbibed fluid continuously dissolving agent which is dispensed fromthe system at a controlled and continuous rate over a prolonged periodof time.
 50. An osmotic system for continuously dispensing an agentaccording to claim 49 wherein the laminated wall comprises a lamina thatis substantially impermeable to agent in the compartment and tocompounds in the environment of use.
 51. The osmotic system forcontinuously dispensing an agent according to claim 49 wherein thelaminated wall comprises a lamina next to the compartment that isessentially non-erodible and inert in the presence of agent.
 52. Theosmotic system for continuously dispensing an agent according to claim49 wherein the laminated wall comprises a lamina distant from thecompartment that is essentially non-erodible and inert in theenvironment of use.
 53. The osmotic system for continuously dispensingan agent according to claim 49 wherein the laminated wall comprisesthree laminae.
 54. The osmotic system for continuously dispensing anagent according to claim 49 wherein the agent has limited solubility inthe fluid and is mixed with an osmotically effective compound thatexhibits an osmotic pressure gradient across the laminated wall againstthe fluid.
 55. The osmotic system for continuously dispensing an agentaccording to claim 49 wherein the inner lamina is a member selected fromthe group consisting of cellulose ethers, cellulose esters,polyurethanes and polyamides.
 56. An osmotic system for the continuousdispensing of an active agent to an environment of use comprising:a. ashaped laminated wall comprising at least two laminae comprising onelamina made of a multiplicity of materials and one lamina made of asemipermeable material, said laminae forming a laminated wall that ispermeable to the passage of an external fluid and substantiallyimpermeable to the passage of agent with the wall surrounding andforming; b. a compartment containing an active agent; c. a passagewaythrough the wall communicating with the compartment and the exterior ofthe system for dispensing agent from the system; and d. wherein inoperation when the system is placed in the environment of use, fluidfrom the environment is continuously imbided through the laminated wall,having a total thickness h_(t), into the compartment in a tendencytowards osmotic equilibrium at a rate proportional to the fluidtransmission rate (kπ)_(t) of the laminated wall which rate is governedby the following equation: ##EQU6## wherein h₁, h₂ and h _(n) are thethickness of the individual lamina, and (kπ)₁, (kπ)₂ and (kπ)_(n) arethe fluid transmission rates for the respective laminae, said imbibedfluid continuously dissolving agent that is dispensed from the system ata controlled and continuous rate over a prolonged period of time.
 57. Anosmotic system for continuously dispensing an agent according to claim56 wherein the laminated wall comprises a lamina that is substantiallyimpermeable to agent in the compartment and to compounds in theenvironment of use.
 58. An osmotic system for continuously dispensing anagent according to claim 56 wherein the laminated wall comprises alamina formed of a multiplicity of materials and positioned next to thecompartment, said lamina being essentially non-erodible and inert in thepresence of agent.
 59. An osmotic system for continuously dispensing anagent according to claim 56 wherein the laminated wall comprises alamina formed of a semipermeable material and positioned next to thecompartment, said lamina being essentially non-erodible and inert in thepresence of agent.
 60. An osmotic system for continuously dispensing anagent according to claim 56 wherein the laminated wall comprises alamina formed of a multiplicity of materials and positioned distant fromthe compartment, said lamina being essentially non-erodible and inert inthe environment of use.
 61. An osmotic system for continuouslydispensing an agent according to claim 56 wherein the laminated wallcomprises a lamina formed of a semipermeable material and positioneddistant from the compartment, said lamina being essentially non-erodibleand inert in the environment of use.
 62. An osmotic system forcontinuously dispensing an agent according to claim 56 wherein thelaminated wall comprises three laminae.
 63. An osmotic system forcontinuously dispensing an agent according to claim 56 wherein the agenthas limited solubility in the fluid and is mixed with an osmoticallyeffective compound that exhibits an osmotic pressure gradient across thelaminated wall against the fluid.